Inhibitors of bruton&#39;s tyrosine kinase

ABSTRACT

This application discloses compounds according to generic Formula (I): wherein all variables are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are useful for the treatment of oncological, auto-immune, and inflammatory diseases caused by aberrant B-cell activation. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application of PCT/EP2014/077116filed Dec. 10, 2014, which claims priority from U.S. Provisional PatentApplication No. 61/915,588, filed on Dec. 13, 2013. Each of the priormentioned applications is hereby incorporated by reference herein in itsentirety.

FIELD OF THE INVENTION

The present invention relates to the use of novel compounds whichinhibit Btk and are useful for the treatment of oncological,auto-immune, and inflammatory diseases caused by aberrant B-cellactivation.

BACKGROUND OF THE INVENTION

Protein kinases constitute one of the largest families of human enzymesand regulate many different signaling processes by adding phosphategroups to proteins (T. Hunter, Cell 1987 50:823-829). Specifically,tyrosine kinases phosphorylate proteins on the phenolic moiety oftyrosine residues. The tyrosine kinase family includes members thatcontrol cell growth, migration, and differentiation. Abnormal kinaseactivity has been implicated in a variety of human diseases includingcancers, autoimmune and inflammatory diseases. Since protein kinases areamong the key regulators of cell signaling they provide a target tomodulate cellular function with small molecular kinase inhibitors andthus make good drug design targets. In addition to treatment ofkinase-mediated disease processes, selective and efficacious inhibitorsof kinase activity are also useful for investigation of cell signalingprocesses and identification of other cellular targets of therapeuticinterest.

There is good evidence that B-cells play a key role in the pathogenesisof autoimmune and/or inflammatory disease. Protein-based therapeuticsthat deplete B cells such as Rituxan are effective againstautoantibody-driven inflammatory diseases such as rheumatoid arthritis(Rastetter et al. Annu Rev Med 2004 55:477). Therefore inhibitors of theprotein kinases that play a role in B-cell activation should be usefultherapeutics for B-cell mediated disease pathology such as autoantibodyproduction.

Signaling through the B-cell receptor (BCR) controls a range of B-cellresponses including proliferation and differentiation into matureantibody producing cells. The BCR is a key regulatory point for B-cellactivity and aberrant signaling can cause deregulated B-cellproliferation and formation of pathogenic autoantibodies that lead tomultiple autoimmune and/or inflammatory diseases. Bruton's TyrosineKinase (Btk) is a non-BCR associated kinase that is membrane proximaland immediately downstream from BCR. Lack of Btk has been shown to blockBCR signaling and therefore inhibition of Btk could be a usefultherapeutic approach to block B-cell mediated disease processes.

Btk is a member of the Tec family of tyrosine kinases, and has beenshown to be a critical regulator of early B-cell development and matureB-cell activation and survival (Khan et al. Immunity 1995 3:283;Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of Btk in humansleads to the condition X-linked agammaglobulinemia (XLA) (reviewed inRosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol.Rev. 2005 203:200). These patients are immunocompromized and showimpaired maturation of B-cells, decreased immunoglobulin and peripheralB-cell levels, diminished T-cell independent immune responses as well asattenuated calcium mobilization following BCR stimulation.

Evidence for a role for Btk in autoimmune and inflammatory diseases hasalso been provided by Btk-deficient mouse models. In preclinical murinemodels of systemic lupus erythematosus (SLE), Btk-deficient mice showmarked amelioration of disease progression. In addition, Btk-deficientmice are resistant to collagen-induced arthritis (Jails son and HolmdahlClin. Exp. Immunol. 1993 94:459). A selective Btk inhibitor hasdemonstrated dose-dependent efficacy in a mouse arthritis model (Z. Panet al., Chem. Med Chem. 2007 2:58-61).

Btk is also expressed by cells other than B-cells that may be involvedin disease processes. For example, Btk is expressed by mast cells andBtk-deficient bone marrow-derived mast cells demonstrate impairedantigen-induced degranulation (Iwaki et al. J. Biol. Chem. 2005280:40261). This shows that Btk could be useful to treat pathologicalmast cells responses such as allergy and asthma. Also monocytes from XLApatients, in which Btk activity is absent, show decreased TNF alphaproduction following stimulation (Horwood et al. J. Exp. Med. 2003197:1603). Therefore TNF alpha-mediated inflammation could be modulatedby small molecular Btk inhibitors. Also, Btk has been reported to play arole in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49) and thusBtk inhibitors would be useful for the treatment of certain B-celllymphomas and leukemias (Feldhahn et al. J. Exp. Med. 2005 201:1837).

SUMMARY OF THE INVENTION

The present application provides the Btk inhibitor compounds of FormulaI, methods of use thereof, as described herein below:

The application provides a compound of Formula I,

wherein:R¹ is lower alkyl, phenyl, cycloalkyl, or pyridyl, optionallysubstituted with one or more R^(1′);

-   -   each R^(1′) is independently lower alkyl, halo, —C(═O)NH₂, or        cyano;        R² is absent, halo, lower alkoxy, hydroxy, or lower alkyl;        R³ is absent, halo, lower alkoxy, hydroxy, or lower alkyl;        R⁴ is absent or heterocycloalkyl lower alkylenyl;        X is CH or N; and        Y is CH or N;        or a pharmaceutically acceptable salt thereof.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I, admixed with at least one pharmaceuticallyacceptable carrier, excipient or diluent.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components.

As used herein, unless specifically indicated otherwise, the word “or”is used in the “inclusive” sense of “and/or” and not the “exclusive”sense of “either/or”.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formuladepicting and describing compounds employed or claimed in the presentinvention, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such compounds result in stablecompounds.

The symbols “*” at the end of a bond or “------” drawn through a bondeach refer to the point of attachment of a functional group or otherchemical moiety to the rest of the molecule of which it is a part. Thus,for example:

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen atom or a substituent.

The phrase “optional bond” means that the bond may or may not bepresent, and that the description includes single, double, or triplebonds. If a substituent is designated to be a “bond” or “absent”, theatoms linked to the substituents are then directly connected.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

Certain compounds of Formulae I may exhibit tautomerism. Tautomericcompounds can exist as two or more interconvertable species. Prototropictautomers result from the migration of a covalently bonded hydrogen atombetween two atoms. Tautomers generally exist in equilibrium and attemptsto isolate an individual tautomers usually produce a mixture whosechemical and physical properties are consistent with a mixture ofcompounds. The position of the equilibrium is dependent on chemicalfeatures within the molecule. For example, in many aliphatic aldehydesand ketones, such as acetaldehyde, the keto form predominates while; inphenols, the enol form predominates. Common prototropic tautomersinclude keto/enol (—C(═O)—CH—⇄—C(—OH)═CH—), amide/imidic acid(—C(═O)—NH—⇄—C(—OH)═N—) and amidine (—C(═NR)—NH—⇄—C(—NHR)═N—) tautomers.The latter two are particularly common in heteroaryl and heterocyclicrings and the present invention encompasses all tautomeric forms of thecompounds.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference are made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

The definitions described herein may be appended to formchemically-relevant combinations, such as “heteroalkylaryl”,“haloalkylheteroaryl”, “arylalkylheterocyclyl”, “alkylcarbonyl”,“alkoxyalkyl”, and the like. When the term “alkyl” is used as a suffixfollowing another term, as in “phenylalkyl,” or “hydroxyalkyl,” this isintended to refer to an alkyl group, as defined above, being substitutedwith one to two substituents selected from the other specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below. The term -(ar)alkyl refersto either an unsubstituted alkyl or an aralkyl group. The term(hetero)aryl or (het)aryl refers to either an aryl or a heteroarylgroup.

The term “spirocycloalkyl”, as used herein, means a spirocycliccycloalkyl group, such as, for example, spiro[3.3]heptane. The termspiroheterocycloalkyl, as used herein, means a spirocyclicheterocycloalkyl, such as, for example, 2,6-diaza spiro[3.3]heptane.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term C₁₋₆ acyl refers to a group—C(═O)R contain 6 carbon atoms. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The term “ester” as used herein denotes a group of formula —C(═O)ORwherein R is lower alkyl as defined herein.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl”, or “hydroxyalkyl”, this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” denotes the radical R′R″—, wherein R′ is a phenyl radical,and R″ is an alkylene radical as defined herein with the understandingthat the attachment point of the phenylalkyl moiety will be on thealkylene radical. Examples of arylalkyl radicals include, but are notlimited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl”or “aralkyl” are interpreted similarly except R′ is an aryl radical. Theterms “(het)arylalkyl” or “(het)aralkyl” are interpreted similarlyexcept R′ is optionally an aryl or a heteroaryl radical.

The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refersto a straight or branched chain hydrocarbon residue containing 1 to 6carbon atoms wherein one or more carbon atoms are substituted with oneor more halogen atoms.

The term “alkylene” or “alkylenyl” as used herein denotes a divalentsaturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g.,(CH₂)_(n)) or a branched saturated divalent hydrocarbon radical of 2 to10 carbon atoms (e.g., —CHMe- or —CH₂CH(i-Pr)CH₂—), unless otherwiseindicated. Except in the case of methylene, the open valences of analkylene group are not attached to the same atom. Examples of alkyleneradicals include, but are not limited to, methylene, ethylene,propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene,2-ethylbutylene.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an —O-alkyl wherein alkyl is C₁₋₁₀.

The term “PCy₃” refers to a phosphine trisubstituted with three cyclicmoieties.

The terms “haloalkoxy” or “halo-lower alkoxy” or “lower haloalkoxy”refers to a lower alkoxy group, wherein one or more carbon atoms aresubstituted with one or more halogen atoms.

The term “hydroxyalkyl” as used herein denotes an alkyl radical asherein defined wherein one to three hydrogen atoms on different carbonatoms is/are replaced by hydroxyl groups.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refers to agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” asused herein refers herein denotes a group of formula —S(═O)₂R wherein Ris “heteroalkyl” as defined herein.

The terms “alkylsulfonylamino” and “arylsulfonylamino” as used hereinrefers to a group of formula —NR'S(═O)₂R wherein R is alkyl or arylrespectively, R′ is hydrogen or C₁₋₃ alkyl, and alkyl and aryl are asdefined herein.

The term “cycloalkyl” as used herein refers to a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to a cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term carboxy-alkyl as used herein refers to an alkyl moiety whereinone, hydrogen atom has been replaced with a carboxyl with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom. The term “carboxy” or “carboxyl” refers to a—CO₂H moiety.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic or partially unsaturated ring containing four to eight atomsper ring, incorporating one or more N, O, or S heteroatoms, theremaining ring atoms being carbon, with the understanding that theattachment point of the heteroaryl radical will be on an aromatic orpartially unsaturated ring. As well known to those skilled in the art,heteroaryl rings have less aromatic character than their all-carboncounter parts. Thus, for the purposes of the invention, a heteroarylgroup need only have some degree of aromatic character. Examples ofheteroaryl moieties include monocyclic aromatic heterocycles having 5 to6 ring atoms and 1 to 3 heteroatoms include, but is not limited to,pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, 4,5-Dihydro-oxazolyl,5,6-Dihydro-4H-[1,3]oxazolyl, isoxazole, thiazole, isothiazole,triazoline, thiadiazole and oxadiaxoline which can optionally besubstituted with one or more, preferably one or two substituentsselected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy,alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen,amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino andarylcarbonylamino. Examples of bicyclic moieties include, but are notlimited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl,5,6,7,8-Tetrahydro-[1,6]naphthyridinyl, and benzisothiazole. Bicyclicmoieties can be optionally substituted on either ring, however the pointof attachment is on a ring containing a heteroatom.

The term “heterocyclyl”, “heterocycloalkyl” or “heterocycle” as usedherein denotes a monovalent saturated cyclic radical, consisting of oneor more rings, preferably one to two rings, including spirocyclic ringsystems, of three to eight atoms per ring, incorporating one or morering heteroatoms (chosen from N, O or S(O)₀₋₂), and which can optionallybe independently substituted with one or more, preferably one or twosubstituents selected from hydroxy, oxo, cyano, lower alkyl, loweralkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof, unlessotherwise indicated. Examples of heterocyclic radicals include, but arenot limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl,pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, andionic forms thereof. Examples may also be bicyclic, such as, forexample, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane,or octahydro-pyrazino[2,1-c][1,4]oxazine.

Inhibitors of Btk

The application provides a compound of Formula I,

wherein:R¹ is lower alkyl, phenyl, cycloalkyl, or pyridyl, optionallysubstituted with one or more R^(1′);

-   -   each R^(1′) is independently lower alkyl, halo, —C(═O)NH₂, or        cyano;        R² is absent, halo, lower alkoxy, hydroxy, or lower alkyl;        R³ is absent, halo, lower alkoxy, hydroxy, or lower alkyl;        R⁴ is absent or heterocycloalkyl lower alkylenyl;        X is CH or N; and        Y is CH or N;        or a pharmaceutically acceptable salt thereof.

The application provides a compound of Formula I, wherein Y is CH.

The application provides either of the above compounds of Formula I,wherein X is N.

The application alternatively provides either of the above compounds ofFormula I, wherein X is CH.

The application provides any of the above compounds of Formula I,wherein R⁴ is morpholinyl methylene.

The application alternatively provides any of the above compounds ofFormula I, wherein R⁴ is absent.

The application provides any of the above compounds of Formula I,wherein R² is absent.

The application alternatively provides any of the above compounds ofFormula I, wherein R² is halo.

The application alternatively provides any of the above compounds ofFormula I, wherein R² is lower alkyl.

The application alternatively provides any of the above compounds ofFormula I, wherein R² is lower alkoxy.

The application alternatively provides any of the above compounds ofFormula I, wherein R² is hydroxy.

The application provides any of the above compounds of Formula I,wherein R³ is halo, lower alkoxy, or hydroxy.

The application provides any of the above compounds of Formula I,wherein R¹ is phenyl, optionally substituted with one or more R^(1′).

The application alternatively provides any of the above compounds ofFormula I, wherein R¹ is lower alkyl, cycloalkyl, or heteroaryl,optionally substituted with one or more R^(1′).

The application provides a compound of Formula I, selected from thegroup consisting of:

-   [5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   {5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;-   {5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;-   5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   {5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   [5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;-   {5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;-   {5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;-   2-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile;-   3-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile;-   3-{4-[5-Amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide;-   {5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone;-   [5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone;    and-   3-{4-[5-Amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating rheumatoid arthritiscomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compound of Formula I.

The application provides a method for treating cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I, admixed with at least one pharmaceuticallyacceptable carrier, excipient or diluent.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of an inflammatorydisorder.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of an autoimmune disorder.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of rheumatoid arthritis.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of asthma.

The application provides the use of a compound as described above forthe treatment of inflammatory and/or autoimmune condition.

The application provides the use of a compound as described above forthe treatment of rheumatoid arthritis.

The application provides the use of a compound as described above forthe treatment of asthma.

The application provides a compound as described above for use in thetreatment of inflammatory and/or autoimmune condition.

The application provides a compound as described above for use in thetreatment of rheumatoid arthritis.

The application provides a compound as described above for use in thetreatment of asthma.

The application provides a compound, method, or composition as describedherein.

The application provides the invention as hereinbefore described.

Compounds and Preparation

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOM™ v. 4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

TABLE I depicts examples of compounds according to generic Formula I:

TABLE I Compound Nomenclature Structure I-1 [5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H- pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-2 [5-Amino-1-(6-phenoxy- pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)- methanone

I-3 {5-Amino-1-[4-(pyridin-2- yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)- methanone

I-4 {5-Amino-1-[4-(pyridin-3- yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)- methanone

I-5 5-Amino-1-(3-chloro-4- phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-6 {5-Amino-1-[4-(3,4- difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol- 2-yl)-methanone

I-7 [5-Amino-1-(3-methoxy-4- phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-8 [5-Amino-1-(3-hydroxy-4- phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-9 [5-Amino-1-(2-methoxy-4- phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-10 [5-Amino-1-(2-hydroxy-4- phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-11 [5-Amino-1-(4-isopropoxy- phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

I-12 [5-Amino-1-(4- cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2- yl)-methanone

I-13 {5-Amino-1-[4-(2,2- dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol- 2-yl)-methanone

I-14 {5-Amino-1-[4-(2,3- difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}- (1H-indol-2-yl)-methanone

I-15 2-{4-[5-Amino-4-(1H- indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}- benzonitrile

I-16 3-{4-[5-Amino-4-(1H- indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}- benzonitrile

I-17 3-{4-[5-Amino-4-(1H- benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl- phenoxy}-benzamide

I-18 {5-Amino-1-[4-(2,3-difluoro- phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H- benzoimidazol-2-yl)- methanone

I-19 [5-Amino-1-(4-phenoxy- phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H- indol-2-yl)-methanone

I-20 3-{4-[5-Amino-4-(6- morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol- 1-yl]-3-chloro-phenoxy}- benzonitrile

General Synthetic Schemes

The compounds of the present invention may be prepared by anyconventional means. Suitable processes for synthesizing these compoundsare provided in the examples. Generally, compounds of the invention maybe prepared according to the schemes below.

Compounds of formula 14, where R1 and R2 are as described above in thegenus of formula I, may be prepared using the route outlined inScheme 1. According to this procedure, the compound of formula 1,4-bromomethyl-benzoic acid methyl ester, which is commerciallyavailable, may be converted to a benzyl amine to give a compound offormula 2. Reduction of the ester provides the benzyl alcohol derivative4 which can be oxidized to the aldehyde derivative 5. Reaction withazido-acetic acid ethyl ester gives the acrylic acid methyl esterderivative 7 which can be cyclized to the corresponding indolederivative 8. Protection of the indole ring with standard protectinggroups such as tosyl (Ts) or 2-(trimethylsilyl)ethoxymethyl (SEM)affords compound of formula 9. The ester 9 may then be reacted with ananion derived from acetonitrile to give the cyanoacetyl derivative offormula 10. Reaction with dimethylformamide dimethyl acetal provides theacrylonitrile derivative 11 and this reacts with the phenylhydrazinederivative of formula 12 to give the aminopyrazole of formula 13.Removal of the protective group then provides the compound of theinvention of formula 14.

4-Bromomethyl-benzoic acid methyl ester, the compound of formula 1, maybe conveniently treated with a base such as di-isopropyl ethylamine inan inert solvent such as tetrahydrofuran at a temperature around 0° C.in the presence of morpholine. The mixture can be stirred at roomtemperature for reaction times between one hour and several hours.Conditions for such a reaction may be found in the literature, forexample in Moore, Jason L. et al. Arkivoc, 2005, 6, 287-292.

The compound of formula 3 may be conveniently converted to the benzylalcohol derivative of formula 4 by treating it with a reducing agentsuch as sodium borohydride in a mixture of solvent such astetrahydrofuran and methanol. The mixture can be stirred under refluxfor reaction times between two hours and several hours.

The compound of formula 4 may be conveniently converted to the aldehydederivative of formula 5 by treating it with an oxidizing agent such asmanganese dioxide in a solvent such as dichloromethane The mixture canbe stirred at room temperature for several hours.

The condensation reaction between aldehyde 5 and azido-acetic acid ethylester 6 can occur at a temperature around 0° C. in presence of sodiummethoxide using a solvent such as methanol. The mixture can be stirredfor reaction times between 30 minutes or several hours.

The formation of the indole 8 can be accomplished using theHemetsberger-Knittel synthesis starting from the acrylic acid methylester derivative 7. Using solvent such as xylene or toluene, thereaction mixture is heated at high temperatures (90° C. or above) forseveral hours. Other methods are available in the literature to performthe cyclization. See Stokes et al., J. Am. Chem. Soc. 2007, 129,7500-7501 described a mild procedure using rhodium(II) perfluorobutyrateas catalyst. See also Tetrahedron Letters 2009, 50, 1708-1709.Alternatively, the indole ring can be synthesized using differentsynthetic methods. For a review, see Chem. Rev. 2006, 106, 2875-2911.

The compound of formula 8, may be conveniently treated with a base suchas sodium hydride in an inert solvent such as tetrahydrofuran at atemperature around 0° C. to generate the corresponding anion. This maybe treated with a protecting group such as tosyl chloride or2-(trimethylsilyl)ethoxymethyl chloride and the mixture stirred at roomtemperature for about an hour to give the derivative of formula 9.

The compound of formula 9 may be conveniently converted to thecyanoacetyl derivative of formula 10 by treating it with a mixture ofacetonitrile and a strong base such as lithium diisopropylamide orlithium hexamethyldisilazide in a solvent such as tetrahydrofuran at lowtemperature, such as at about −78° C. Conditions for such a reaction maybe found in the patent literature, for example in Taka, N. et al. US20120208811 Page 163.

The compound of formula 10 may be converted to the acrylonitrilederivative of formula 11 by treatment with N,N-dimethylformamidedimethyl acetal in an inert solvent such as an aromatic hydrocarbon(e.g., toluene) or tetrahydrofuran at about room temperature. Conditionsfor such a reaction may be found in the patent literature, for examplein Taka, N. et al. US 20120208811 page 132.

The acrylonitrile derivative of formula 11 may be converted to theaminopyrazole derivative of formula 13 by treatment with an intermediateof formula 12, where R1 and R2 are as described above in the genus offormula I, in an alcoholic solvent such as methanol or ethanol orisopropanol, at about the reflux temperature of the solvent. Conditionsfor such a reaction may be found in the patent literature, for examplein Taka, N. et al. US 20120208811 Page 94.

The conversion of the compound of formula 13 to the compound of theinvention of formula 14 may be effected using any conventionalprocedure. For example, in the case of a tosyl protecting group, thereaction may be carried out by treating the compound of formula 13 witha mixture of a base such as cesium carbonate and a lower alcohol such asmethanol in a solvent such a tetrahydrofuran at a temperature betweenabout room temperature and about the reflux temperature of the mixture.Examples of conditions that may be used for such a reaction can be foundin the literature, for example in Zhang, B and Wee. A. G. H. Org.Biomol. Chem. 2012, 10, 4597-4608 Supplementary Information; in Alam, M.et al. US 20110071150 page 54; and in Taka, N. et al. US 20120208811Page 55. For example, in the case of a SEM protecting group, thereaction may be carried out by treating the compound of formula 13 witha mixture of tetrabutylammonium fluoride and ethylenediamine in asolvent such as tetrahydrofuran or dimethylformamide at a temperaturebetween about 50° C. and about the reflux temperature of the mixture.Examples of conditions that may be used for such a reaction can be foundin the literature, for example in Barrett, T. D. et al. WO 2004007463Page 182; in Kerns, J. K. et al. WO 2007062318 Page 47; and in Degnan,A. P. et al. US 20090018132 Page 119. Alternatively, the compound offormula 14 may be treated with concentrated hydrochloric acid in analcoholic solvent (such as methanol, ethanol, or isopropanol) or intetrahydrofuran at the reflux temperature to give the compound of theinvention of formula 14. Examples of conditions that may be used forsuch a reaction can be found in the literature, for example in Muneau,Y. et al. US 20080262020 Page 24.

Intermediates of formula 12 where R1 and R2 are as described above inthe genus of formula I, may be prepared according to scheme 2. Thecompound of formula 15 undergoes a nucleophilic aromatic substitutionreaction with a phenol derivative of formula 16 to give a compound offormula 17. Reduction of the nitro group in the compound of formula 18,followed by diazotization and reduction gives the aryl-hydrazinederivative of formula 12.

4-Chloro-1-nitro-benzene derivatives such as compound 15 may be treatedwith a phenol of formula 16 in the presence of a base such as potassiumcarbonate or cesium carbonate in an inert solvent such asdimethylformamide at a temperature between about 100° C. and about 150°C., optionally under microwave irradiation, to give a nitro compound offormula 17. Examples of particular conditions that may be used for sucha reaction may be found in the literature, for example in Chee, G.-L etal. US 20040266738 Page 5; and in Cui, S.-L. et al. Synlett 2004,1829-1831.

The reduction of the nitro group in the compound of formula 17 can beeffected using a variety of procedures well known to one of averageskill in the field of organic synthesis. Many of these procedures areoutlined in Larock, R. C. Comprehensive Organic Transformations JohnWiley & Sons Inc. NY 1999, pp. 823 et seq. One convenient approach is totreat the compound of formula 17 with hydrogen gas in the presence of anoble metal catalyst such as palladium-on-carbon in a solvent such analcohol (e.g., methanol or ethanol) at a pressure between about oneatmosphere of hydrogen and about three atmospheres of hydrogen at aboutroom temperature. Examples of particular conditions that may be used forsuch a reaction may be found in the literature, for example in Chee,G.-L et al. US 20040266738 Page 5; and in Schoenafinger, K. et al. US20030236288 Page 18.

The diazotization and reduction of the aniline group in the compound offormula 17 may be carried out using any conventional procedure. Forexample, the reaction is conveniently carried out by treating thecompound of formula 18 with sodium nitrite in aqueous solution in thepresence of an inorganic acid such as hydrochloric acid at a temperaturebelow about 5° C. and preferably below about 0° C., followed by theaddition of a reducing agent such as tin(II) chloride or sodiumdithionite at about the same temperature. Examples of particularconditions that may be used for such a reaction may be found in theliterature, for example in Wipf, P. and Qiming, J. WO 2012078859 page47; in Rewolinski, M. V. et al. WO 2009055721 page 82; and inSchoenafinger, K. et al. US 20030236288 page 18.

Compounds of formula 7, where R1 and R2 are as described above in thegenus of formula I, may be prepared using the route outlined inScheme 1. According to this procedure, the compound of formula 1, whichare commercially available, may be protected using a protecting groupsuch as a tosyl (Ts) or a 2-(trimethylsilyl)ethoxymethyl (SEM) to give acompound of formula 2. The ester 2 may then be reacted with an anionderived from acetonitrile to give the cyanoacetyl derivative of formula3. Reaction with dimethylformamide dimethyl acetal provides theacrylonitrile derivative 4 and this reacts with the phenylhydrazinederivative of formula 5 to give the aminopyrazole of formula 6. Removalof the protective group then provides the compound of the invention offormula 7.

Ethyl 1H-indole-2-carboxylate and ethyl1H-benzo[d]imidazole-2-carboxylate, compounds of formula 1, may beconveniently treated with a base such as sodium hydride in an inertsolvent such as tetrahydrofuran at a temperature around 0° C. togenerate the corresponding anion. This may be treated with tosylchloride or 2-(trimethylsilyl)ethoxymethyl chloride and the mixturestirred at room temperature for about an hour to give the derivative offormula 2.

The compound of formula 2 may be conveniently converted to thecyanoacetyl derivative of formula 3 by treating it with a mixture ofacetonitrile and a strong base such as lithium diisopropylamide orlithium hexamethyldisilazide in a solvent such as tetrahydrofuran at lowtemperature, such as at about −78° C. Conditions for such a reaction maybe found in the patent literature, for example in Taka, N. et al. US20120208811 Page 163.

The compound of formula 3 may be converted to the acrylonitrilederivative of formula 4 by treatment with N,N-dimethylformamide dimethylacetal in an inert solvent such as an aromatic hydrocarbon (e.g.,toluene) or tetrahydrofuran at about room temperature. Conditions forsuch a reaction may be found in the patent literature, for example inTaka, N. et al. US 20120208811 page 132.

The acrylonitrile derivative of formula 4 may be converted to theaminopyrazole derivative of formula 6 by treatment with an intermediateof formula 5, where R1 and R2 are as described above in the genus offormula I, in an alcoholic solvent such as methanol or ethanol orisopropanol, at about the reflux temperature of the solvent. Conditionsfor such a reaction may be found in the patent literature, for examplein Taka, N. et al. US 20120208811 Page 94.

The conversion of the compound of formula 6 to the compound of theinvention of formula 7 may be effected using any conventional procedure.For example, in the case of a tosyl protecting group, the reaction maybe carried out by treating the compound of formula 6 with a mixture of abase such as cesium carbonate and a lower alcohol such as methanol in asolvent such a tetrahydrofuran at a temperature between about roomtemperature and about the reflux temperature of the mixture. Examples ofconditions that may be used for such a reaction can be found in theliterature, for example in Zhang, B and Wee. A. G. H. Org. Biomol. Chem.2012, 10, 4597-4608 Supplementary Information; in Alam, M. et al. US20110071150 page 54; and in Taka, N. et al. US 20120208811 Page 55. Forexample, in the case of a SEM protecting group, the reaction may becarried out by treating the compound of formula 6 with a mixture oftetrabutylammonium fluoride and ethylenediamine in a solvent such astetrahydrofuran or dimethylformamide at a temperature between about 50°C. and about the reflux temperature of the mixture. Examples ofconditions that may be used for such a reaction can be found in theliterature, for example in Barrett, T. D. et al. WO 2004007463 Page 182;in Kerns, J. K. et al. WO 2007062318 Page 47; and in Degnan, A. P. etal. US 20090018132 Page 119. Alternatively, the compound of formula 7may be treated with concentrated hydrochloric acid in an alcoholicsolvent (such as methanol, ethanol, or isopropanol) or intetrahydrofuran at the reflux temperature to give the compound of theinvention of formula 7. Examples of conditions that may be used for sucha reaction can be found in the literature, for example in Muneau, Y. etal. US 20080262020 Page 24.

Intermediates of formula 5 where R1 and R2 are as described above in thegenus of formula I, may be prepared according to scheme 2. The compoundof formula 8 undergoes a nucleophilic aromatic substitution reactionwith an alcohol derivative of formula 9 to give a compound of formula10. Reduction of the nitro group in the compound of formula 11, followedby diazotization and reduction gives the aryl-hydrazine derivative offormula 5.

4-Chloro-1-nitro-benzene derivatives such as compound 8 may be treatedwith an alcohol (phenol or alkyl alcohol) of formula 9 in the presenceof a base such as potassium carbonate or cesium carbonate in an inertsolvent such as dimethylformamide at a temperature between about 100° C.and about 150° C., optionally under microwave irradiation, to give anitro compound of formula 10. Examples of particular conditions that maybe used for such a reaction may be found in the literature, for examplein Chee, G.-L et al. US 20040266738 Page 5; and in Cui, S.-L. et al.Synlett 2004, 1829-1831.

The reduction of the nitro group in the compound of formula 10 can beeffected using a variety of procedures well known to one of averageskill in the field of organic synthesis. Many of these procedures areoutlined in Larock, R. C. Comprehensive Organic Transformations JohnWiley & Sons Inc. NY 1999, pp. 823 et seq. One convenient approach is totreat the compound of formula 10 with hydrogen gas in the presence of anoble metal catalyst such as palladium-on-carbon in a solvent such analcohol (e.g., methanol or ethanol) at a pressure between about oneatmosphere of hydrogen and about three atmospheres of hydrogen at aboutroom temperature. Examples of particular conditions that may be used forsuch a reaction may be found in the literature, for example in Chee,G.-L et al. US 20040266738 Page 5; and in Schoenafinger, K. et al. US20030236288 Page 18.

The diazotization and reduction of the aniline group in the compound offormula 11 may be carried out using any conventional procedure. Forexample, the reaction is conveniently carried out by treating thecompound of formula 11 with sodium nitrite in aqueous solution in thepresence of an inorganic acid such as hydrochloric acid at a temperaturebelow about 5° C. and preferably below about 0° C., followed by theaddition of a reducing agent such as tin(II) chloride or sodiumdithionite at about the same temperature. Examples of particularconditions that may be used for such a reaction may be found in theliterature, for example in Wipf, P. and Qiming, J. WO 2012078859 page47; in Rewolinski, M. V. et al. WO 2009055721 page 82; and inSchoenafinger, K. et al. US 20030236288 page 18.

Pharmaceutical Compositions and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatin capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell-known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polyactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Indications and Methods of Treatment

The compounds of generic Formula I inhibit Bruton's tyrosine kinase(Btk). Activation of Btk by upstream kinases results in activation ofphospholipase-Cγ which, in turn, stimulates release of pro-inflammatorymediators. Compounds of Formula I are useful in the treatment ofarthritis and other anti-inflammatory and auto-immune diseases.Compounds according to Formula I are, accordingly, useful for thetreatment of arthritis. Compounds of Formula I are useful for inhibitingBtk in cells and for modulating B-cell development. The presentinvention further comprises pharmaceutical compositions containingcompounds of Formula I admixed with pharmaceutically acceptable carrier,excipients or diluents.

The compounds described herein are kinase inhibitors, in particular Btkinhibitors. These inhibitors can be useful for treating one or morediseases responsive to kinase inhibition, including diseases responsiveto Btk inhibition and/or inhibition of B-cell proliferation, in mammals.Without wishing to be bound to any particular theory, it is believedthat the interaction of the compounds of the invention with Btk resultsin the inhibition of Btk activity and thus in the pharmaceutical utilityof these compounds. Accordingly, the invention includes a method oftreating a mammal, for instance a human, having a disease responsive toinhibition of Btk activity, and/or inhibiting B-cell proliferation,comprising administrating to the mammal having such a disease, aneffective amount of at least one chemical entity provided herein. Aneffective concentration may be ascertained experimentally, for exampleby assaying blood concentration of the compound, or theoretically, bycalculating bioavailability. Other kinases that may be affected inaddition to Btk include, but are not limited to, other tyrosine kinasesand serine/threonine kinases.

Kinases play notable roles in signaling pathways controlling fundamentalcellular processes such as proliferation, differentiation, and death(apoptosis). Abnormal kinase activity has been implicated in a widerange of diseases, including multiple cancers, autoimmune and/orinflammatory diseases, and acute inflammatory reactions. Themultifaceted role of kinases in key cell signaling pathways provides asignificant opportunity to identify novel drugs targeting kinases andsignaling pathways.

An embodiment includes a method of treating a patient having anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction responsive to inhibition of Btk activity and/or B-cellproliferation.

Autoimmune and/or inflammatory diseases that can be affected usingcompounds and compositions according to the invention include, but arenot limited to: psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, Sjogren's disease, tissue graft rejection, and hyperacuterejection of transplanted organs, asthma, systemic lupus erythematosus(and associated glomerulonephritis), dermatomyositis, multiplesclerosis, scleroderma, vasculitis (ANCA-associated and othervasculitides), autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathicthrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease,Alzheimer's disease, diabetes, septic shock, and myasthenia gravis.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

B-cells and B-cell precursors expressing BTK have been implicated in thepathology of B-cell malignancies, including, but not limited to, B-celllymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma),hairy cell lymphoma, multiple myeloma, chronic and acute myelogenousleukemia and chronic and acute lymphocytic leukemia.

BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) deathinducing signaling complex (DISC) in B-lineage lymphoid cells. The fateof leukemia/lymphoma cells may reside in the balance between theopposing proapoptotic effects of caspases activated by DISC and anupstream anti-apoptotic regulatory mechanism involving BTK and/or itssubstrates (Vassilev et al., J. Biol. Chem. 1998, 274, 1646-1656).

It has also been discovered that BTK inhibitors are useful aschemosensitizing agents, and, thus, are useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.Examples of other chemotherapeutic drugs that can be used in combinationwith chemosensitizing BTK inhibitors include topoisomerase I inhibitors(camptothecin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), and biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines).

Btk activity has also be associated with some leukemias expressing thebcr-abl fusion gene resulting from translocation of parts of chromosome9 and 22. This abnormality is commonly observed in chronic myelogenousleukemia. Btk is constitutively phosphorylated by the bcr-abl kinasewhich initiates downstream survival signals which circumvents apoptosisin bcr-abl cells. (N. Feldhahn et al. J. Exp. Med. 2005201(11):1837-1852).

Methods of Treatment

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating an inflammatory conditioncomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating rheumatoid arthritiscomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of Formula I.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the Btk inhibitor compoundof Formulae I.

The application provides a method for treating arthritis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the Btk inhibitor compound of Formula I.

The application provides a method for treating cancer comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the Btk inhibitor compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the Btk inhibitor compound of Formula I.

The application provides a method of inhibiting B-cell proliferationcomprising administering to a patient in need thereof a therapeuticallyeffective amount of the Btk inhibitor compound of Formula I.

The application provides a method for inhibiting Btk activity comprisingadministering the Btk inhibitor compound of any one of Formula I,wherein the Btk inhibitor compound exhibits an IC₅₀ of 50 micromolar orless in an in vitro biochemical assay of Btk activity.

In one variation of the above method, the Btk inhibitor compoundexhibits an IC₅₀ of 100 nanomolar or less in an in vitro biochemicalassay of Btk activity.

In another variation of the above method, the compound exhibits an IC₅₀of 10 nanomolar or less in an in vitro biochemical assay of Btkactivity.

The application provides a method for treating an inflammatory conditioncomprising co-administering to a patient in need thereof atherapeutically effective amount of an anti-inflammatory compound incombination with the Btk inhibitor compound of Formula I.

The application provides a method for treating arthritis comprisingco-administering to a patient in need thereof a therapeuticallyeffective amount of an anti-inflammatory compound in combination withthe Btk inhibitor compound of Formula I.

The application provides a method for treating a lymphoma or a BCR-ABL1⁺leukemia cells by administering to a patient in need thereof atherapeutically effective amount of the Btk inhibitor compound ofFormula I.

EXAMPLES

General Abbreviations

Commonly used abbreviations include: acetyl (Ac),azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm),9-borabicyclo[3.3.1]nonane (9-BBN or BBN), 2, 2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tert-butoxycarbonyl (Boc),di-tert-butyl pyrocarbonate or boc anhydride (BOC₂O), benzyl (Bn), butyl(Bu), Chemical Abstracts Registration Number (CASRN), benzyloxycarbonyl(CBZ or Z), carbonyl diimidazole (CDI), 1, 4-diazabicyclo[2.2.2]octane(DABCO), diethylaminosulfur trifluoride (DAST), dibenzylideneacetone(dba), 1, 5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), N, N′-dicyclohexylcarbodiimide(DCC), 1, 2-dichloroethane (DCE), dichloromethane (DCM), 2,3-Dichloro-5, 6-dicyano-1, 4-benzoquinone (DDQ), diethylazodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD),di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine(DIPEA), N, N-dimethyl acetamide (DMA), 4-N, N-dimethylaminopyridine(DMAP), N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,1′-bis-(diphenylphosphino)ethane (dppe), 1,1′-bis-(diphenylphosphino)ferrocene (dppf),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline (EEDQ), ethyl (Et),ethyl acetate (EtOAc), ethanol (EtOH),2-ethoxy-2H-quinoline-1-carboxylic acid ethyl ester (EEDQ), diethylether (Et₂O), ethyl isopropyl ether (EtOiPr),0-(7-azabenzotriazole-1-yl)-N, N, N′N′-tetramethyluroniumhexafluorophosphate acetic acid (HATU), acetic acid (HOAc),1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography(HPLC), iso-propanol (IPA), isopropylmagnesium chloride (iPr mgCl),hexamethyl disilazane (HMDS), liquid chromatography mass spectrometry(LCMS), lithium hexamethyl disilazane (LiHMDS), meta-chloroperoxybenzoicacid (m-CPBA), methanol (MeOH), melting point (mp), MeSO₂— (mesyl orMs), methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA),mass spectrum (ms), methyl t-butyl ether (MTBE), methyl tetrahydrofuran(MeTHF), N-bromosuccinimide (NBS), n-Butyllithium (nBuLi),N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine(NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC),Dichloro-((bis-diphenylphosphino)ferrocenyl) palladium (II) (Pd(dppf)Cl₂), palladium (II) acetate (Pd(OAc)₂), tris(dibenzylideneacetone)dipalladium (0) (Pd₂ (dba)₃), pyridiniumdichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), poundsper square inch (psi), pyridine (pyr), 1, 2, 3, 4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-Phos), roomtemperature (ambient temperature, rt or RT), sec-Butyllithium (sBuLi),tert-butyldimethylsilyl or t-BuMe₂Si (TBDMS), tetra-n-butylammoniumfluoride (TBAF), triethylamine (TEA or Et₃N), 2, 2, 6,6-tetramethylpiperidine 1-oxyl (TEMPO), trimethylsilylethoxymethyl(SEM), triflate or CF₃SO₂— (Tf), trifluoroacetic acid (TFA), 1,1′-bis-2,2, 6, 6-tetramethylheptane-2,6-dione (TMHD), O-benzotriazol-1-yl-N, N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), thin layerchromatography (TLC), tetrahydrofuran (THF), trimethylsilyl or Me₃Si(TMS), p-toluenesulfonic acid monohydrate (TsOH or pTsOH), 4-Me-C₆H₄SO₂—or tosyl (Ts), and N-urethane-N-carboxyanhydride (UNCA). Conventionalnomenclature including the prefixes normal (n), iso (i-), secondary(sec-), tertiary (tert-) and neo have their customary meaning when usedwith an alkyl moiety. (J. Rigaudy and D. P. Klesney, Nomenclature inOrganic Chemistry, IUPAC 1979 Pergamon Press, Oxford).

General Conditions

Compounds of the present invention can be prepared beginning with thecommercially available starting materials by utilizing general synthetictechniques and procedures known to those skilled in the art. Outlinesbelow are reaction schemes suitable for preparing such compounds.Further exemplification can be found in the specific examples.

Specific Abbreviations

CDCl₃ Deuterated chloroform

CH₂Cl₂ Dichloromethane

CH₃CN Acetonitrile

CO₂ Carbon dioxide

Conc Concentrated

Cs₂CO₃ Cesium carbonate

DIPEA Diisopropylethylamine

DMF N,N-Dimethylformamide

DMSO Dimethylsulfoxide

EtOAc Ethyl acetate

EtOH Ethanol

HCl Hydrochloric acid

K₂CO₃ Potassium carbonate

LDA Lithium diisopropylamide

LiAlH₄ Lithium aluminum hydride

MeOH Methanol

NaBH₄ Sodium borohydride

NaOH Sodium hydroxide

Na₂SO₄ Sodium sulfate

NaH Sodium hydride

NaNO₂ Sodium nitrite

Pd(OAc)₂ Palladium(II) acetate

Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0)

SOCl₂ Thionyl chloride

SEM 2-(Trimethylsilyl)ethoxymethyl

SEM-Cl 2-trimethylsilyl)ethoxymethyl chloride

THF Tetrahydrofuran

General Experimental Details

Reagents were purchased from Aldrich, Oakwood, Matrix or other suppliersand used without further purification. Reactions using microwaveirradiation for heating were conducted using either a Personal ChemistryEmrys Optimizer System or a CEM Discovery System. The purification ofmulti-milligram to multi-gram scale was conducted by methods known knowto those skilled in the art such as elution of silica gel flash column;preparative flash column purifications were also effected in some casesby use of disposal pre-packed multigram silica gel columns (RediSep)eluted with a CombiFlash system. Biotage™ and ISCO™ are also flashcolumn instruments that may have been used in this invention forpurification of intermediates.

For the purpose of judging compound identity and purity, LC/MS (liquidchromatography/mass spectroscopy) spectra were recorded using thefollowing system. For measurement of mass spectra, the system consistsof a Micromass Platform II spectrometer: ES Ionization in positive mode(mass range: 150-1200). The simultaneous chromatographic separation wasachieved with the following HPLC system: ES Industries Chromegabond WRC-18 3u 120 Å (3.2×30 mm) column cartridge; Mobile Phase A: Water (0.02%TFA) and Phase B: Acetonitrile (0.02% TFA); gradient 10% B to 90% B in 3minutes; equilibration time of 1 minute; flow rate of 2 mL/minute.

Many compounds of Formula 1 were also purified by reversed phased HPLC,using methods well known to those skilled in the art. In some cases,preparative HPLC purification was conducted using PE Sciex 150 EX MassSpec controlling a Gilson 215 collector attached to a Shimadzupreparative HPLC system and a Leap autoinjector. Compounds werecollected from the elution stream using LC/MS detection in the positiveion detection: The elution of compounds from C-18 columns (2.0×10 cmeluting at 20 mL/min) was effected using appropriate linear gradationmode over 10 minutes of Solvent (A) 0.05% TFA/H₂O and Solvent (B) 0.035%TFA/acetonitrile. For injection on to HPLC systems, the crude sampleswere dissolved in mixtures of methanol, acetonitrile and DMSO.

¹H-NMR characterization was performed using Bruker or Varian 300 or 400MHz NMR Spectrometers.

The compounds of the present invention may be synthesized according toknown techniques. The following examples and references are provided toaid the understanding of the present invention. The examples are notintended, however, to limit the invention, the true scope of which isset forth in the appended claims. The names of the final products in theexamples were generated using Isis AutoNom 2000.

Intermediate 1(E)-3-Dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile

Step 1) 1-(Toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester

To a stirred solution 1H-Indole-2-carboxylic acid ethyl ester (1 g, 5.29mmol) in dry THF at 0° C. was added sodium hydride in 60% oil dispersion(0.423 g, 10.58 mmol) and stirred for 30 min. To this mixture was addedp-toluene sulfonyl chloride (2 g, 10.58 mmol) and stirred for 12 h. Itwas quenched with saturated ammonium chloride, extracted with ethylacetate, dried over anhydrous sodium sulfate, evaporated under reducedpressure and the crude material was purified by column chromatography(silica gel, 5% EtOAc/Hexanes) to provide1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as whitesolid (1.1 g, 61%). MS calcd. for C₁₈H₁₇NO₄S [(M+H)⁺] 344, obsd. 344.1.

Step 2) 3-Oxo-3-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-propionitrile

To a stirred solution of 1-(toluene-4-sulfonyl)-1H-indole-2-carboxylicacid ethyl ester (8 g, 23.3 mmol) and acetonitrile (3.8 mL, 93.3 mmol)in dry THF (40 mL) at −78° C. was added drop wise LDA (47.3 ml, 46.64mmol) [prepared from addition of n-BuLi (25.6 mL, 46.64 mmol) to asolution of di-isopropyl amine (6.7 mL, 46.6 mmol) in dry THF (15 mL) at−78° C. and stirred for 30 min under argon]. It was stirred for 20 min,quenched with ammonium chloride (10 mL), concentrated, extracted withethyl acetate, dried over anhydrous sodium sulfate, evaporated underreduced pressure and purified by column chromatography (silica gel, 30%EtOAc/Hexanes) to provide3-oxo-3-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-propionitrile as stickybrown liquid (5.7 g, 72%). MS calcd. for C₁₈H₁₄N₂O₃S [(M+H)⁺] 339, obsd.339.0.

Step 3)(E)-3-Dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile

DMF-DMA (0.72 g, 7.09 mmol) was added to a stirred solution of3-oxo-3-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-propionitrile (2 g, 5.91mmol) in toluene (30 mL) at rt and stirred for 15 h. The solvent wasevaporated under reduced pressure and the crude material was purified bycolumn chromatography (silica gel, 30% EtOAc/Hexanes) to provide(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrileas yellow solid (1.2 g, 52%). MS calcd. for C₂₁H₁₉N₃O₃S [(M+H)⁺] 394,obsd. 394.3.

Intermediate 2(E)-3-Dimethylamino-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-acrylonitrile

Step 1) 1-(2-Trimethylsilanyl-ethoxymethyl)-1H-indole-2-carboxylic acidethyl ester

In a 250 mL round-bottomed flask, ethyl 1H-indole-2-carboxylate (5 g,26.4 mmol), SEM-Cl (5.29 g, 5.62 mL, 31.7 mmol) and NaH in 60% oildispersion (1.27 g, 31.7 mmol) were combined at 4° C. with THF (40 mL)and DMF (20 mL). The reaction mixture was stirred and let warmed to roomtemperature for 5 hours. The reaction mixture was quenched with MeOH,diluted with water and EtOAc. The solution was washed with brine, thecombined organic phases were dried over anhydrous sodium sulfate and thesolvent was removed under reduced pressure. The crude material waspurified by column chromatography (silica gel, 0-40% EtOAc/hexanes) togive 1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carboxylic acidethyl ester (6.8 g, 81%) as an orange oil. ¹H NMR (300 MHz, DMSO-d₆) δ7.69 (t, J=7.63 Hz, 2H), 7.31-7.41 (m, 2H), 7.17 (t, J=7.50 Hz, 1H),5.96 (s, 2H), 4.32 (q, J=7.16 Hz, 2H), 3.43 (t, J=7.82 Hz, 2H), 1.33 (t,J=7.06 Hz, 3H), 0.76 (t, J=7.82 Hz, 2H), −0.14 (s, 9H).

Step 2)3-Oxo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-propionitrile

In a 500 mL round-bottomed flask, ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carboxylate (5 g, 15.7mmol), acetonitrile (3.93 g, 5 mL, 95.7 mmol) were combined with THF (75mL) at −78° C. under a nitrogen atmosphere to give an orange solution.LDA 2M in THF (10 mL, 20.0 mmol) was added at −78° C. and the reactionmixture was stirred and let warmed to room temperature. The reaction wascomplete after 2 hours 30 minutes. The reaction mixture was diluted withwater and EtOAc and washed with brine. The combined organic phases weredried over anhydrous sodium sulfate and the solvent was removed underreduced pressure. The crude material was purified by columnchromatography (silica gel, 0-40% EtOAc/hexanes) to give3-oxo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-propionitrile(3.9 g, 79%) as an oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.77 (d, J=7.91 Hz,1H), 7.65-7.72 (m, 2H), 7.44 (t, J=7.63 Hz, 1H), 7.21 (t, J=7.44 Hz,1H), 5.93 (s, 2H), 4.75 (s, 2H), 1.17 (t, J=7.16 Hz, 2H), 0.78 (t,J=7.91 Hz, 2H), −0.12 (s, 9H).

Step 3)(E)-3-Dimethylamino-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-acrylonitrile

In a 250 mL round-bottomed flask,3-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-2-yl)propanenitrile(3.8 g, 12.1 mmol) and DMF-DMA (7 mL, 52.3 mmol) were combined withtoluene (30 mL) to give a light yellow solution. The reaction mixturewas stirred at room temperature overnight. The solvent was removed underreduced pressure. The crude material was purified by columnchromatography (silica gel, 0-100% EtOAc/hexanes) to give(E)-3-dimethylamino-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-acrylonitrile(3.5 g, 78%) as an orange foam. ¹H NMR (300 MHz, DMSO-d₆) δ 8.03 (s,1H), 7.69 (d, J=7.91 Hz, 1H), 7.63 (d, J=8.29 Hz, 1H), 7.32 (t, J=7.25Hz, 1H), 7.12-7.19 (m, 2H), 5.78 (s, 2H), 3.40 (s, 3H), 3.31-3.35 (m,2H), 3.30 (s, 3H), 0.75 (t, J=8.01 Hz, 2H), −0.13 (s, 9H).

Intermediate 3(E)-3-Dimethylamino-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carbonyl]-acrylonitrile

Step 1)1-(2-Trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carboxylic acidethyl ester

In a 250 mL round-bottomed flask, ethyl1H-benzo[d]imidazole-2-carboxylate (3 g, 15.8 mmol), SEM-Cl (3.36 mL,18.9 mmol) and NaH in 60% oil dispersion (760 mg, 31.7 mmol) werecombined with THF (25 mL) and DMF (10 mL) to give a white suspension.The reaction mixture was stirred at room temperature for 3 hours. Thereaction was quenched with water. The reaction mixture was diluted withEtOAc and washed with brine. The combined organic phases were dried overanhydrous sodium sulfate and the solvent was removed under reducedpressure. The crude material was purified by column chromatography(silica gel, 0-40% EtOAc/hexanes) to give1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carboxylic acidethyl ester (2.7 g, 53%) as an oil. LC/MS: m/z calculated forC₁₆H₂₄N₂O₃Si ([M+H]⁺): 321.4. Found: 321.0.

Step 2)3-Oxo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propionitrile

In a 100 mL round-bottomed flask, ethyl1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carboxylate(2 g, 6.24 mmol) and acetonitrile (2.56 g, 3.26 ml, 62.4 mmol) werecombined with THF (40 mL) at −78° C. under a nitrogen atmosphere to givea light brown solution. LDA 2M in THF (5 mL, 10.0 mmol) was added at−78° C. and the reaction mixture was stirred and let warmed to roomtemperature. The reaction mixture was stirred at this temperature for 4hours, then the reaction mixture was poured over a solution of sataqueous NH₄Cl solution and extracted with EtOAc. The combined organicphases were dried over anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 0-40% EtOAc/hexanes to give3-Oxo-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-propionitrile(0.6 g, 31%) as an oil. ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=8.10 Hz,1H), 7.78-7.84 (m, 1H), 7.49-7.57 (m, 1H), 7.38-7.47 (m, 1H), 5.87-6.09(m, 2H), 4.86 (s, 2H), 3.41-3.71 (m, 2H), 0.68-0.94 (m, 2H), −0.1 (s,9H)

Step 3)(E)-3-Dimethylamino-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carbonyl]-acrylonitrile

In a 20 mL scintillation vial,3-oxo-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)propanenitrile(500 mg, 1.59 mmol) and DMF-DMA (0.85 mL, 6.34 mmol) were combined withtoluene (5 mL) to give a yellow solution. The reaction mixture wasstirred at room temperature overnight. The solvent was removed underreduced pressure. The crude material was purified by columnchromatography (silica gel, 0-100% EtOAc/hexanes) to give(E)-3-Dimethylamino-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carbonyl]-acrylonitrile(0.26 g, 44%) as an orange foam. LC/MS: m/z calculated for C₁₉H₂₆N₄O₂Si([M+H]⁺): 371.5. Found: 371.0.

General Procedure A: Nucleophilic Aromatic Substitution

Cs₂CO₃ (1.5 equivalents) was added to a stirred solution of the nitrocompound (1 equivalent) and the phenol or alkyl alcohol derivatives (1.2equivalents) in dry DMF. The mixture was heated in a sealed tube at 150°C. for 24 h. The reaction mixture was filtered, and the filtrate wasevaporated under reduced pressure. The residue was purified bychromatography on silica gel to give the product.

General Procedure B: Reduction of the Nitro Group

10% Palladium on carbon (10% by weight) was added to a stirred solutionof the nitro compound in ethanol under nitrogen atmosphere. The reactionmixture was stirred under a hydrogen atmosphere for 12 h, filteredthrough sintered funnel and evaporated under reduced pressure to get thecorresponding amine.

General Procedure C-1: Preparation of Arylhydrazines

A solution of sodium nitrite (1.5 equivalents) in water was added to astirred solution of the aminoaromatic compound (1 equivalent) inhydrochloric acid at −5° C. and the mixture was stirred at −5° C. for 45min. A solution of tin(II) chloride (5 equivalents) in hydrochloric acidwas added and the mixture was stirred for 30 min. The mixture was madealkaline by adding aqueous NaOH solution, and the mixture was extractedwith EtOAc. The organic extract was dried (Na₂SO₄), filtered, andevaporated to give the product which was used directly in the next step.

General Procedure C-2: Preparation of Arylhydrazines

A solution of sodium nitrite (1.5 equivalents) in water was added to astirred solution of the aminoaromatic compound (1 equivalent) inhydrochloric acid at −5° C. and the mixture was stirred at −5° C. for 45min. A solution of tin(II) chloride (5 equivalents) in hydrochloric acidwas added and the mixture was stirred for 30 min. The mixture wasfiltered and dried under air to give the product which was used directlyin the next step.

General Procedure D: Pyrazole Ring Formation

A mixture of an arylhydrazine of formula Ar—NH—NH2 (2 equivalents) and(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for intermediate 1 Step 3; 1equivalent) in EtOH was heated at reflux for 16 h. The solvent wasevaporated under reduced pressure. The residue was purified bychromatography on silica gel to give the product.

General Procedure E: Deprotection of the Ts Protective Group

To a stirred solution of the Ts-protected indole (1 equivalent) inTHF:MeOH (7:3) was added cesium carbonate (2 equivalents). The mixturewas stirred at room temperature for 18 h. The solvent was evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel to give the product.

Example 1[5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 2-Fluoro-4-nitro-1-phenoxy-benzene

1-Bromo-2-fluoro-4-nitrobenzene was reacted with phenol using theconditions outlined in General Procedure A to give2-fluoro-4-nitro-1-phenoxy-benzene.

Step 2) 3-Fluoro-4-phenoxy-phenylamine

2-Fluoro-4-nitro-1-phenoxy-benzene was reduced using the conditionsoutlined in General Procedure B to give 3-fluoro-4-phenoxy-phenylamine.MS calcd. for C₁₂H₁₁FNO [(M+H)⁺] 204, obsd. 204.2.

Step 3) (3-Fluoro-4-phenoxy-phenyl)-hydrazine

3-Fluoro-4-phenoxy-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give(3-fluoro-4-phenoxy-phenyl)-hydrazine.

Step 4)[5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(3-Fluoro-4-phenoxy-phenyl)-hydrazine was reacted with(E)-3-Dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1, Step 3) usingthe conditions outlined in General Procedure D to give[5-amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₁H₂₃FN₄O₄S [(M+H)⁺] 567, obsd. 567.1.

Step 5)[5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₄H₇FN₄O₂ [(M+H)⁺] 413, obsd. 413.1.

Example 2[5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 5-Nitro-2-phenoxy-pyridine

2-Chloro-5-nitro-pyridine was reacted with phenol using the conditionsoutlined in General Procedure A to give 5-nitro-2-phenoxy-pyridine.

Step 2) 6-Phenoxy-pyridin-3-ylamine

5-Nitro-2-phenoxy-pyridine was reduced using the conditions outlined inGeneral Procedure B to give 6-phenoxy-pyridin-3-ylamine. MS calcd. forC₁₁H₁₀N₂O [(M+H)⁺] 187, obsd. 187.1.

Step 3) (6-Phenoxy-pyridin-3-yl)-hydrazine

6-Phenoxy-pyridin-3-ylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give(6-phenoxy-pyridin-3-yl)-hydrazine.

Step 4)[5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(6-Phenoxy-pyridin-3-yl)-hydrazine was reacted with(E)-3-Dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3) using theconditions outlined in General Procedure D to give[5-amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₀H₂₃N₅O₄S [(M+H)⁺]550, obsd. 550.2.

Step 5)[5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₃H₁₇N₅O₂S [(M+H)⁺]396, obsd. 396.1.

Example 3{5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

Step 1) 2-(4-Nitro-phenoxy)-pyridine

1-Chloro-4-nitro-benzene was reacted with pyrindin-2-ol using theconditions outlined in General Procedure A to give2-(4-nitro-phenoxy)-pyridine. MS calcd. for C₁₁H₈N₂O₃ [(M+H)⁺]217, obsd.217.1.

Step 2) 4-(Pyridin-2-yloxy)-phenylamine

2-(4-Nitro-phenoxy)-pyridine was reduced using the conditions outlinedin General Procedure B to give 4-(pyridin-2-yloxy)-phenylamine. MScalcd. for C₁₁H₁₀N₂O [(M+H)⁺]187, obsd. 187.3.

Step 3) [4-(Pyridin-2-yloxy)-phenyl]-hydrazine

4-(Pyridin-2-yloxy)-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give[4-(pyridin-2-yloxy)-phenyl]-hydrazine.

Step 4){5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

[4-(Pyridin-2-yloxy)-phenyl]-hydrazine was reacted with(E)-3-Dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3) using theconditions outlined in General Procedure D to give{5-amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₀H₂₃N₅O₄S [(M+H)⁺]550, obsd. 550.0.

Step 5){5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

{5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give{5-amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone.MS calcd. for C₂₃H₁₇N₅O₂S [(M+H)⁺]396, obsd. 395.9.

Example 4{5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

Step 1) 3-(4-Nitro-phenoxy)-pyridine

1-Chloro-4-nitro-benzene was reacted with pyrindin-3-ol using theconditions outlined in General Procedure A to give3-(4-Nitro-phenoxy)-pyridine. MS calcd. for C₁₁H₈N₂O₃ [(M+H)⁺]217, obsd.217.2.

Step 2) 4-(Pyridin-3-yloxy)-phenylamine

3-(4-Nitro-phenoxy)-pyridine was reduced using the conditions outlinedin General Procedure B to give 4-(pyridin-3-yloxy)-phenylamine. MScalcd. for C₁₁H₁₀N₂O [(M+H)⁺]187, obsd. 187.4.

Step 3) [4-(Pyridin-3-yloxy)-phenyl]-hydrazine

4-(Pyridin-3-yloxy)-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give[4-(pyridin-3-yloxy)-phenyl]-hydrazine.

Step 4){5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

[4-(Pyridin-3-yloxy)-phenyl]-hydrazine was reacted with(E)-3-Dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3) using theconditions outlined in General Procedure D to give{5-amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₀H₂₃N₅O₄S [(M+H)⁺]550, obsd. 550.3.

Step 5){5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

{5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give{5-amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone.MS calcd. for C₂₃H₁₇N₅O₂S [(M+H)⁺]396, obsd. 396.4.

Example 55-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 2-Chloro-4-nitro-1-phenoxy-benzene

1,2-Dichloro-4-nitro-benzene was reacted with phenol using theconditions outlined in General Procedure A to give2-chloro-4-nitro-1-phenoxy-benzene. MS calcd. for C₁₂H₈ClNO₃[(M+H)⁺]250, obsd. 249.9.

Step 2) 3-Chloro-4-phenoxy-phenylamine

2-Chloro-4-nitro-1-phenoxy-benzene was reduced using the conditionsoutlined in General Procedure B to give 3-chloro-4-phenoxy-phenylamine.

Step 3) (3-Chloro-4-phenoxy-phenyl)-hydrazine

3-Chloro-4-phenoxy-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give(3-chloro-4-phenoxy-phenyl)-hydrazine.

Step 4)[5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(3-Chloro-4-phenoxy-phenyl)-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3) using theconditions outlined in General Procedure D to give[5-amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₁H₂₃ClN₄O₄S [(M+H)⁺]584, obsd. 585.2.

Step 5)[5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₄H₁₇ClN₄O₂ [(M+H)⁺]429, obsd. 429.4.

Example 6{5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

Step 1) 3,4-Difluoro-3-(4-nitro-phenoxy)-benzene

1-Chloro-4-nitro-benzene was reacted with 3,4-difluoro-phenol using theconditions outlined in General Procedure A to give3,4-difluoro-3-(4-nitro-phenoxy)-benzene. MS calcd. for C₁₂H₇F₂NO₃[(M+H)⁺]252, obsd. 252.0.

Step 2) 4-(3,4-Difluoro-phenoxy)-phenylamine

1,2-Difluoro-3-(4-nitro-phenoxy)-benzene was reduced using theconditions outlined in General Procedure B to give4-(3,4-difluoro-phenoxy)-phenylamine

Step 3) [4-(3,4-Difluoro-phenoxy)-phenyl]-hydrazine

4-(2,3-difluoro-phenoxy)-phenylamine was diazotized and reduced usingthe conditions outlined in General Procedure C-1 to give[4-(3,4-difluoro-phenoxy)-phenyl]-hydrazine.

Step 4){5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

[4-(3,4-Difluoro-phenoxy)-phenyl]-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1, Step 3) usingthe conditions outlined in General Procedure D to give{5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

Step 5){5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

{5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give{5-amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone.MS calcd. for C₂₄H₁₆F₂N₄O₂ [(M+H)⁺]431, obsd. 431.3.

Example 7[5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 2-Methoxy-4-nitro-1-phenoxy-benzene

1-Chloro-2-methoxy-4-nitro-benzene was reacted with phenol using theconditions outlined in General Procedure A to give2-methoxy-4-nitro-1-phenoxy-benzene. MS calcd. for C₁₃H₁₁NO₄[(M+H)⁺]246, obsd. 246.0.

Step 2) 3-Methoxy-4-phenoxy-phenylamine

2-Methoxy-4-nitro-1-phenoxy-benzene was reduced using the conditionsoutlined in General Procedure B to give 3-methoxy-4-phenoxy-phenylamine

Step 3) (3-Methoxy-4-phenoxy-phenyl)-hydrazine

3-Methoxy-4-phenoxy-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give(3-methoxy-4-phenoxy-phenyl)-hydrazine.

Step 4)[5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(3-Methoxy-4-phenoxy-phenyl)-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3) using theconditions outlined in General Procedure D to give[5-amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₂H₂₆N₄O₅S [(M+H)⁺]579, obsd. 579.1.

Step 5)[5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₅H₂₀N₄O₃ [(M+H)⁺]425, obsd. 425.3.

Example 8[5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1)[5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

To a solution of[5-amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone(150 mg, 0.296 mmol) in DCM (8 mL) was added BBr₃ (0.103 mL, 1.04 mmol)at 0° C. and stirred for 30 min. TLC showed complete consumption ofstarring material, the mixture was then quenched with aqueous NaOHsolution and extracted with DCM. The organic layer was washed withwater, dried over anhydrous sodium sulfate and concentrated. The crudematerial was purified by column chromatography (silica gel, 25%EtOAc/Hexanes) to give[5-amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone(100 mg, 68%) as yellowish solid. MS calcd. for C₃₁H₂₄N₄O₅S [(M+H)⁺]565,obsd. 565.3.

Step 2)[5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₄H₁₈N₄O₃ [(M+H)⁺]411, obsd. 411.2.

Example 9[5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 2-Methoxy-1-nitro-4-phenoxy-benzene

1-Chloro-3-methoxy-4-nitro-benzene was reacted with phenol using theconditions outlined in General Procedure A to give2-methoxy-1-nitro-4-phenoxy-benzene. MS calcd. for C₁₃H₁₁NO₄[(M+H)⁺]246, obsd. 246.0.

Step 2) 2-Methoxy-4-phenoxy-phenylamine

2-Methoxy-1-nitro-4-phenoxy-benzene was reduced using the conditionsoutlined in General Procedure B to give 2-methoxy-4-phenoxy-phenylamine

Step 3) (2-Methoxy-4-phenoxy-phenyl)-hydrazine

2-Methoxy-4-phenoxy-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give(2-methoxy-4-phenoxy-phenyl)-hydrazine.

Step 4)[5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(2-Methoxy-4-phenoxy-phenyl)-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3 using theconditions outlined in General Procedure D to give[5-amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₂H₂₆N₄O₅S [(M+H)⁺]579, obsd. 579.1.

Step 5)[5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₅H₂₀N₄O₃ [(M+H)⁺]425, obsd. 425.3.

Example 10[5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1)[5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

To a solution of[5-amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone(150 mg, 0.296 mmol) in DCM (8 mL) was added BBr₃ (0.103 mL, 1.04 mmol)at 0° C. and stirred for 30 min. TLC showed complete consumption ofstarring material, the mixture was then quenched with aqueous NaOHsolution and extracted with DCM. The organic layer was washed withwater, dried over anhydrous sodium sulfate and concentrated. The crudematerial was purified by column chromatography (silica gel, 25%EtOAc/Hexanes) to give[5-amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone(100 mg, 68%) as yellowish solid. MS calcd. for C₃₁H₂₄N₄O₅S [(M+H)⁺]565,obsd. 565.3.

Step 2)[5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₄H₁₈N₄O₃ [(M+H)⁺]411, obsd. 411.3.

Example 11[5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 1-Isopropoxy-4-nitro-benzene

1-Chloro-4-nitro-benzene was reacted with isopropanol using theconditions outlined in General Procedure A to give1-isopropoxy-4-nitro-benzene. MS calcd. for C₉H₁₁NO₃ [(M+H)⁺]182, obsd.182.2.

Step 2) 4-Isopropoxy-phenylamine

1-isopropoxy-4-nitro-benzene was reduced using the conditions outlinedin General Procedure B to give 4-isopropoxy-phenylamine

Step 3) (4-Isopropoxy-phenyl)-hydrazine

4-Isopropoxy-phenylamine was diazotized and reduced using the conditionsoutlined in General Procedure C-1 to give(4-isopropoxy-phenyl)-hydrazine.

Step 4)[5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(4-Isopropoxy-phenyl)-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3 using theconditions outlined in General Procedure D to give[5-amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₂₈H₂₆N₄O₄S [(M+H)⁺]515, obsd. 515.2.

Step 5)[5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₁H₂₀N₄O₂ [(M+H)⁺]361, obsd. 361.2.

Example 12[5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

Step 1) 1-Cyclopentyloxy-4-nitro-benzene

1-Chloro-4-nitro-benzene was reacted with cyclopentanol using theconditions outlined in General Procedure A to give1-cyclopentyloxy-4-nitro-benzene.

Step 2) 4-Cyclopentyloxy-phenylamine

1-Cyclopentyloxy-4-nitro-benzene was reduced using the conditionsoutlined in General Procedure B to give 4-cyclopentyloxy-phenylamine.

Step 3) (4-Cyclopentyloxy-phenyl)-hydrazine

4-Cyclopentyloxy-phenylamine was diazotized and reduced using theconditions outlined in General Procedure C-1 to give(4-cyclopentyloxy-phenyl)-hydrazine.

Step 4)[5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(4-Cyclopentyloxy-phenyl)-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1, Step 3 using theconditions outlined in General Procedure D to give[5-amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₀H₂₈N₄O₄S [(M+H)⁺]541, obsd. 541.3.

Step 5)[5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone

[5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give[5-amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone.MS calcd. for C₂₃H₂₂N₄O₂ [(M+H)⁺]387, obsd. 387.4.

Example 13{5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

Step 1) 1-(2,2-Dimethyl-propoxy)-4-nitro-benzene

1-Chloro-4-nitro-benzene was reacted with 2,2-dimethyl-propan-1-ol usingthe conditions outlined in General Procedure A to give1-cyclopentyloxy-4-nitro-benzene. MS calcd. for C₁₁H₁₅NO₃ [(M+H)⁺]210,obsd. 210.2.

Step 2) 4-(2,2-Dimethyl-propoxy)-phenylamine

1-(2,2-Dimethyl-propoxy)-4-nitro-benzene was reduced using theconditions outlined in General Procedure B to give4-(2,2-dimethyl-propoxy)-phenylamine.

Step 3) [4-(2,2-Dimethyl-propoxy)-phenyl]-hydrazine

4-(2,2-Dimethyl-propoxy)-phenylamine was diazotized and reduced usingthe conditions outlined in General Procedure C-1 to give[4-(2,2-dimethyl-propoxy)-phenyl]hydrazine.

Step 4){5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

[4-(2,2-Dimethyl-propoxy)-phenyl]-hydrazine was reacted with(E)-3-dimethylamino-2-[1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(which may be prepared as described for Intermediate 1 Step 3 using theconditions outlined in General Procedure D to give{5-amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone.MS calcd. for C₃₀H₃₀N₄O₄S [(M+H)⁺]543, obsd. 543.2.

Step 5){5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

{5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-[1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanonewas reacted with cesium carbonate using the conditions outlined inGeneral Procedure E to give{5-amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone.MS calcd. for C₂₃H₂₄N₄O₂ [(M+H)⁺]389, obsd. 389.2.

Example 14{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

Step 1: 2-Methyl-1-nitro-4-(2,3-difluoro)-phenoxy-benzene

4-Chloro-2-methyl-nitrobenzene was reacted with 2,3-difluoro-phenolusing the conditions outlined in General Procedure A to give2-methyl-1-nitro-4-(2,3-difluoro)-phenoxy-benzene. MS calcd. forC₁₃H₁₀F₂NO₃ [(M+H)⁺] 266, obsd. 266.2

Step 2: 4-(2,3-Difluoro-phenoxy)-2-methyl-phenylamine

2-Methyl-1-nitro-4-(2,3-difluoro)-phenoxy-benzene was reduced using theconditions outlined in General Procedure B to give4-(2,3-difluoro-phenoxy)-2-methyl-phenylamine. MS calcd. for C₁₃H₁₂F₂NO[(M+H)⁺] 236, obsd. 235.8.

Step 3: [4-(2,3-Difluoro-phenoxy)-2-methyl-phenyl]-hydrazine,hydrochloride salt

4-(2,3-Difluoro-phenoxy)-2-methyl-phenylamine was diazotized and reducedusing the conditions outlined in General Procedure C-2 to give[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-hydrazine hydrochloride salt.

Step 4){5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1ethoxymethyl-1H-indol-2-yl)-methanone

In a 20 mL scintillation vial,(E)-3-(dimethylamino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbonyl)acrylonitrile(intermediate 2 Step 3) (200 mg, 0.541 mmol),(4-(2,3-difluorophenoxy)-2-methylphenyl)hydrazine (271 mg, 1.08 mmol)and potassium carbonate (224 mg, 1.62 mmol) were combined with EtOH (4mL) to give a yellow suspension. The reaction mixture was heated at 80°C. overnight. The reaction mixture was diluted with EtOAc and washedwith brine. The combined organic phases were dried over anhydrous sodiumsulfate and the solvent was removed under reduced pressure. The crudematerial was purified by column chromatography (silica gel,EtOAc/Hexanes 0-100%) to provide{5-amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1ethoxymethyl-1H-indol-2-yl)-methanone(165 mg, 79%) as an oil. LC/MS: m/z calculated for C₂₈H₂₄F₂N₄O₃([M+H]⁺): 503.5. Found: 503.1.

Step 5){5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone

In a 20 mL scintillation vial,(5-amino-1-(4-(2,3-difluorophenoxy)-2-methylphenyl)-1H-pyrazol-4-yl)(1-(ethoxymethyl)-1H-indol-2-yl)methanone(100 mg, 0.199 mmol) was combined with EtOH (4 mL) and aq.HCl 10% (2mL). The reaction mixture was heated at 80° C. for 2 hours. The reactionmixture was diluted with EtOAc and washed with brine. The combinedorganic phases were dried over anhydrous sodium sulfate and the solventwas removed under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 0-70% EtOAc-Hexanes) to give{5-amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone(36 mg, 41%) as an oil. LC/MS: m/z calculated for C₂₅H₁₈F₂N₄O₂ ([M+H]⁺):445.4. Found: 444.9.

Example 152-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile

Step 1) 2-(3-Methyl-4-nitro-phenoxy)-benzonitrile

A mixture of 4-fluoro-2-methyl-1-nitro-benzene (13.1 g, 84 mmol),2-hydroxybenzonitrile (10 g, 84 mmol) and K₂CO₃ (23.5 g, 168 mmol) inacetone (100 mL) was heated at 70° C. overnight. Water was added and themixture was extracted with EtOAc. The combined organic layers were driedover anhydrous sodium sulfate, filtered, and evaporated. MeOH was addedand the mixture was allowed to stand at room temperature over theweekend. The solid was filtered to give2-(3-methyl-4-nitro-phenoxy)-benzonitrile (7.5 g, 35%) in two crops as ayellow solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.10 (d, J=8.9 Hz, 1H), 7.75(dd, J=7.7, 1.5 Hz, 1H), 7.56-7.68 (m, 1H), 7.33 (td, J=7.6, 0.9 Hz,1H), 7.09 (d, J=8.5 Hz, 1H), 6.88-7.00 (m, 2H), 2.64 (s, 3H). MS calcd.for C₁₄H₁₁N₂O₃ [(M+H)⁺] 255, obsd. 255.0.

Step 2) 2-(4-Amino-3-methyl-phenoxy)-benzonitrile

A mixture of tin(II) chloride (18.6 g, 98.3 mmol),2-(3-methyl-4-nitro-phenoxy)-benzonitrile (5 g, 19.7 mmol), MeOH (60mL), THF (100 mL) and water (30 mL) was heated at 70° C. for 4 h. Themixture was evaporated and the residue was made basic by adding 10 NNaOH. The resulting mixture was extracted with EtOAc. The organic layerwas dried (Na₂SO₄), filtered, and evaporated. The residue was purifiedby chromatography (silica gel, 0-30% EtOAc/hexanes) to give2-(4-amino-3-methyl-phenoxy)-benzonitrile (3.5 g, 79%) as a solid. MScalcd. for C₁₄H₁₃N₂O [(M+H)⁺] 225, obsd. 224.9.

Step 3) 2-(4-Hydrazino-3-methyl-phenoxy)-benzonitrile hydrochloride salt

A solution of NaNO₂ (1.23 g, 17.8 mmol) in water (10 mL) was added to amixture of 2-(4-amino-3-methyl-phenoxy)-benzonitrile (2 g, 8.92 mmol),HCl (10 mL), water (20 mL) and MeOH (15 mL) at 4° C. The mixture wasstirred for at 4° C. for 45 min. A solution of tin(II) chloride (10 g,44.6 mmol) in conc. HCl (10 mL) was added and the mixture was stirredfor 4 h. The mixture was filtered to give crude2-(4-hydrazino-3-methyl-phenoxy)-benzonitrile hydrochloride salt (600mg, 28%) as a yellow salt. This material was used in the next stepwithout further purification.

Step 4)2-(4-{5-Amino-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile

In a 20 mL scintillation vial,(E)-3-(dimethylamino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbonyl)acrylonitrile(intermediate 2 Step 3) (200 mg, 0.541 mmol),2-(3-hydrazinyl-2-methylphenoxy)benzonitrile hydrochloride salt (200 mg,0.836 mmol) and potassium carbonate (300 mg, 2.17 mmol) were combinedwith EtOH (4 mL) to give a dark red suspension. The reaction mixture washeated at 80° C. overnight. The reaction mixture was diluted with EtOAcand washed with brine. The combined organic phases were dried overanhydrous sodium sulfate and the solvent was removed under reducedpressure. The crude material was purified by column chromatography(silica gel, 0-70% EtOAc-Hexanes) to provide2-(4-{5-amino-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile(160 mg, 52%) as an oil. LC/MS: m/z calculated for C₃₂H₃₃N₅O₃Si([M+H]⁺): 564.7. Found: 564.2.

Step 5)2-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile

In a 20 mL scintillation vial,2-(4-(5-amino-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbonyl)-1H-pyrazol-1-yl)-3-methylphenoxy)benzamide(160 mg, 0.275 mmol, Eq: 1.00), TBAF 1M in THF (5.5 mL, 5.5 mmol, Eq:20) and ethane-1,2-diamine (165 mg, 2.75 mmol, Eq: 10) were combined.The reaction mixture was heated at 70° C. overnight. After 18 hours, thereaction was incomplete. Another 4 mL of TBAF 1M in THF was added andlet stir at 70° C. for an additional 2 hours. The solvent was removedunder reduced pressure. The crude material was diluted with EtOAc andwashed with a saturated NH₄Cl aqueous solution. The combined organicphases were dried over anhydrous sodium sulfate and the solvent wasremoved under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 0-100% EtOAc/Hexanes) to provide2-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile(50 mg, 42%) as a solid. LC/MS: m/z calculated for C₂₆H₁₉N₅O₂ ([M+H]⁺):434.4. Found: 434.0.

Example 163-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile

Step 1) 3-(3-Chloro-4-nitro-phenoxy)-benzonitrile

A mixture of 2-chloro-4-fluoro-1-nitro-benzene (15 g, 85 mmol),3-hydroxybenzonitrile (10.1 g, 85 mmol) and Cs₂CO₃ (30.4 g, 93.5 mmol)in DMF (100 mL) was heated at 120° C. for 1 h. EtOAc was added and themixture was washed with water and brine. The organic layer was dried(Na₂SO₄), filtered, and evaporated to give3-(3-chloro-4-nitro-phenoxy)-benzonitrile (23 g, 99%) as a yellow solid.

Step 2) 3-(4-Amino-3-chloro-phenoxy)-benzonitrile

A solution of tin(II) chloride dihydrate (75.4 g, 335 mmol) in HCl (50mL) was added to a solution of 3-(3-chloro-4-nitro-phenoxy)-benzonitrile(23 g, 83.9 mmol) in MeOH (500 mL) and the mixture was stirred at roomtemperature for 6 h. The mixture was made basic by adding 2 N NaOH, andthe resulting mixture was extracted with EtOAc. The organic layer waswashed with brine, dried (Na₂SO₄), filtered, and evaporated. The residuewas purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to give3-(4-amino-3-chloro-phenoxy)-benzonitrile (13.8 g, 67%) as a yellow oil.

Step 3) 3-(3-Chloro-4-hydrazino-phenoxy)-benzonitrile hydrochloride salt

A mixture of 3-(4-amino-3-chloro-phenoxy)-benzonitrile (5 g, 20.4 mmol)and conc. HCl (30 mL) in MeOH (30 mL) was cooled to −5° C. A solution ofNaNO₂ (1.72 g, 24.5 mmol) in water (2 mL) was added and the mixture wasstirred for 40 min at −5° C. A solution of tin(II) chloride dihydrate(23.1 g, 102 mmol) in HCl (20 mL) was added and the mixture was stirredfor 1 h. The mixture was evaporated and the solid was filtered off anddried under vacuum to give 3-(3-chloro-4-hydrazino-phenoxy)-benzonitrilehydrochloride salt (5.8 g, 96%). This material was used in the next stepwithout further purification.

Step 4)3-{4-[5-Amino-4-(1-ethoxymethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile

In a 20 mL scintillation vial,(E)-3-(dimethylamino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indole-2-carbonyl)acrylonitrile(intermediate 2, step 3) (100 mg, 0.271 mmol), potassium carbonate (112mg, 0.812 mmol) and 3-(3-chloro-4-hydrazinylphenoxy)benzonitrile (217mg, 0.836 mmol) were combined with EtOH (4 mL) to give a yellowsuspension. The reaction mixture was heated at 80° C. overnight. Thereaction mixture was diluted with EtOAc and washed with brine. Thecombined organic phases were dried over anhydrous sodium sulfate and thesolvent was removed under reduced pressure. The crude material waspurified by column chromatography (silica gel, 0-100% EtOAc/hexanes) togive3-{4-[5-amino-4-(1-ethoxymethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile(95 mg, 69%) as an oil. LC/MS: m/z calculated for C₂₈H₂₂ClN₅O₃ ([M+H]⁺):512.9. Found: 511.9.

Step 5)3-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile

In a 20 mL scintillation vial,3-(4-(5-amino-4-(1-(ethoxymethyl)-1H-indole-2-carbonyl)-1H-pyrazol-1-yl)-3-chlorophenoxy)benzonitrile(60 mg, 0.117 mmol) was combined with EtOH (4 mL) and aq.HCl 10% (2 mL).The reaction mixture was heated at 80° C. for 3 hours. The reactionmixture was diluted with EtOAc and washed with brine. The combinedorganic phases were dried over anhydrous sodium sulfate and the solventwas removed under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 0-70% EtOAc/hexanes) to give3-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile(18 mg, 34%) as a light brown solid. LC/MS: m/z calculated forC₂₅H₁₆ClN₅O₂ ([M+H]⁺): 454.8. Found: 454.0.

Example 173-{4-[5-Amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide

Step 1) 3-(3-Methyl-4-nitro-phenoxy)-benzonitrile

A mixture of 4-fluoro-2-methyl-1-nitro-benzene (13.1 g, 84 mmol),3-hydroxybenzonitrile (10 g, 84 mmol) and Cs₂CO₃ (30.1 g, 92 mmol) inDMF (100 mL) was heated at 120° C. for 3 h. Et₂O was added and themixture was washed with water and brine. The organic layer was dried(Na₂SO₄), filtered, and evaporated to give3-(3-methyl-4-nitro-phenoxy)-benzonitrile (19.2 g, 90%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.09 (d, J=8.8 Hz, 1H), 7.71-7.77 (m, 2H), 7.62-7.70(m, 1H), 7.48-7.55 (m, 1H), 7.16 (d, J=2.8 Hz, 1H), 7.04 (dd, J=8.9, 2.9Hz, 1H). MS calcd. for C₁₄H₁₁N₂O₃ [(M+H)⁺]255, obsd. 254.9.

Step 2) 3-(4-Amino-3-methyl-phenoxy)-benzonitrile

A solution of tin(II) chloride dihydrate (34.9 g, 155 mmol) in conc. HCl(35 mL) was added to a solution of3-(3-methyl-4-nitro-phenoxy)-benzonitrile (9.85 g, 38.7 mmol) in MeOH(300 mL) and the mixture was stirred overnight. The mixture wasevaporated and the residue was made basic by adding 2 N NaOH. Theresulting mixture was extracted four times with EtOAc. The organic layerwas washed with water and brine, dried (Na₂SO₄), filtered, andevaporated. The residue was purified by chromatography (silica gel,0-30% EtOAc/hexanes) to give 3-(4-amino-3-methyl-phenoxy)-benzonitrile(4.6 g, 53%) as a black liquid. MS calcd. for C₁₄H₁₃N₂O ([M+H]⁺): 225,obsd. 225.0.

Step 3) 3-(4-Hydrazino-3-methyl-phenoxy)-benzonitrile

A solution of NaNO₂ (340 mg, 4.9 mmol) in water (1 mL) was added to amixture of 3-(4-amino-3-methyl-phenoxy)-benzonitrile (1 g, 4.46 mmol),conc. HCl (2 mL), water (4 mL) and MeOH (2 mL) at 4° C. The mixture wasstirred for 30 min. A solution of tin(II) chloride (4.23 g, 22 mmol) inconc. HCl (10 mL) was added slowly and the mixture was stirred for 3 h.MeOH (10 mL) was added, followed by 10 M NaOH (caution:exotherm). Themixture was cooled, and EtOAc and 10 M NaOH were added. The organicphase was washed with brine, and evaporated to give crude3-(4-hydrazino-3-methyl-phenoxy)-benzonitrile (600 mg, 56%) as ared-brown oil. This material was used in the next step without furtherpurification. MS calcd. for C₁₄H₁₄N₃O ([M+H]⁺): 240, obsd. 222.9.

Step 4)3-(4-{5-Amino-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile

In a 20 mL scintillation vial,(E)-3-(dimethylamino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)acrylonitrile(intermediate 3, step 3) (200 mg, 0.540 mmol),3-(4-hydrazinyl-3-methylphenoxy)benzonitrile (200 mg, 0.836 mmol) andpotassium carbonate (300 mg, 2.17 mmol) were combined with EtOH (4 mL)to give an orange suspension. The reaction mixture was heated at 80° C.overnight. The reaction was incomplete.3-(4-hydrazinyl-3-methylphenoxy)benzonitrile (200 mg, 0.836 mmol, Eq:1.55) were added and the reaction mixture was heated at 80° C. foranother hour. The reaction mixture was diluted with EtOAc and washedwith brine. The combined organic phases were dried over anhydrous sodiumsulfate and the solvent was removed under reduced pressure. The crudematerial was purified by column chromatography (silica gel, 0-70%EtOAc/hexanes) to give3-(4-{5-Amino-4-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole-2-carbonyl]-pyrazol-1-yl}-3-methyl-phenoxy)-benzonitrile(30 mg, 10%) as an oil. LC/MS: m/z calculated for C₃₁H₃₂N₆O₃Si ([M+H]⁺):565.7. Found: 565.1.

Step 5)3-{4-[5-Amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide

In a 20 mL scintillation vial,3-(4-(5-amino-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)-1H-pyrazol-1-yl)-3-methylphenoxy)benzonitrile(30 mg, 0.053 mmol), wet TBAF 1M in THF (13.9 mg, 0.053 mmol) andethane-1,2-diamine (32 mg, 0.53 mmol) were combined with THF (1 mL). Thereaction mixture was heated at 70° C. for 24 hours. The solvent wasremoved under reduced pressure. The crude material was diluted withEtOAc and washed with a saturated NH₄Cl aqueous solution. The combinedorganic phases were dried over anhydrous sodium sulfate and the solventwas removed under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 0-100% EtOAc/hexanes) to give3-{4-[5-amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide(13 mg, 54% yield) as a solid. LC/MS: m/z calculated for C₂₅H₂₀N₆O₃([M+H]⁺): 453.4. Found: 452.9.

Example 18{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone

Step 1){5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-methanone

In a 20 mL scintillation vial,(E)-3-(dimethylamino)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbonyl)acrylonitrile(intermediate 3, step 3) (200 mg, 0.540 mmol),(4-(2,3-difluorophenoxy)-2-methylphenyl)hydrazine (example 14, step 3)(261 mg, 1.04 mmol) and potassium carbonate (224 mg, 1.62 mmol) werecombined with EtOH (5 mL) to give a yellow suspension. The reactionmixture was heated at 80° C. overnight. The reaction mixture was dilutedwith EtOAc and washed with brine. The combined organic phases were driedover anhydrous sodium sulfate and the solvent was removed under reducedpressure. The crude material was purified by column chromatography(silica gel, 0-70% EtOAc/hexanes) to give{5-amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-methanone(40 mg, 13% yield) as an oil. LC/MS: m/z calculated for C₃₀H₃₁F₂N₅O₃Si([M+H]⁺): 576.7. Found: 576.1.

Step 2){5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone

In a 20 mL scintillation vial,(5-amino-1-(4-(2,3-difluorophenoxy)-2-methylphenyl)-1H-pyrazol-4-yl)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methanone(40 mg, 0.070 mmol), ethane-1,2-diamine (42 mg, 0.695 mmol) and TBAF 1Min THF (0.9 mL, 1.8 mmol) were combined with THF (1 mL) to give a lightred solution. The reaction mixture was heated at 70° C. for 24 hours.The solvent was removed under reduced pressure. The crude material wasdiluted with EtOAc and washed with a saturated NH₄Cl aqueous solution.The combined organic phases were dried over anhydrous sodium sulfate andthe solvent was removed under reduced pressure. The crude material waspurified by column chromatography (silica gel, 0-100% EtOAc/hexanes) togive{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone(20 mg, 65% yield) as a solid. LC/MS: m/z calculated for C₂₄H₁₇F₂N₅O₂([M+H]⁺): 446.4. Found: 445.9.

Example 19[5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone

Step 1) 4-Morpholin-4-ylmethyl-benzoic acid methyl ester

Di-isopropyl ethyl amine (15.2 mL, 87.3 mmol) was added to a stirredsolution of morpholine (4.2 mL, 48 mmol) in dry THF (50 mL) at 0° C.4-Bromomethyl-benzoic acid methyl ester (10 g, 87.3 mmol) in dry THF (70mL) was added and stirred for 12 h. The solvent was removed underreduced pressure and diluted with water. The resulting solution wasextracted with ethyl acetate. The combined organic phases were driedover anhydrous sodium sulfate, evaporated under reduced pressure. Thecrude material was purified by column chromatography (silica gel, 30%EtOAc/Hexanes) to give 4-morpholin-4-ylmethyl-benzoic acid methyl ester(10.5 g, 93%) as off white solid. MS calcd. for C₁₃H₁₇NO₃ [(M+H)⁺] 236,obsd. 236.1.

Step 2) (4-Morpholin-4-ylmethyl-phenyl)-methanol

Sodium borohydride (2.57 g, 68 mmol) was added to a stirred solution of4-morpholin-4-ylmethyl-benzoic acid methyl ester (2 g, 8.5 mmol) in amixture of THF: MeOH (8:1) (56 mL) at 0° C. under a nitrogen atmosphere.The reaction mixture was heated to reflux for 2 h. It was quenched withsaturated ammonium chloride solution at 0° C. and stirred for 30 min. Itwas extracted with ethyl acetate (20 mL×2), dried over anhydrous sodiumsulfate, evaporated under reduced pressure and purified by columnchromatography (silica gel, 2% MeOH/DCM) to give(4-morpholin-4-ylmethyl-phenyl)-methanol (1.3 g, 74%) as a white solid.MS calcd. for C₁₂H₁₇NO₂ [(M+H)⁺] 208, obsd. 208.1.

Step 3) 4-Morpholin-4-ylmethyl-benzaldehyde

Manganese dioxide (3.28 g, 37.67 mmol) was added to a stirred solutionof (4-morpholin-4-ylmethyl-phenyl)-methanol (1.3 g, 6.28 mmol) inmethylene dichloride (120 mL) at rt and stirred for 72 h. The reactionmixture was filtered through sintered funnel using celite and washedwith methylene dichloride (50 mL). The solvent was evaporated underreduced pressure and purified by column chromatography (silica gel, 20%EtOAc/Hexanes) to give 4-morpholin-4-ylmethyl-benzaldehyde (1.2 g, 93%)as a white solid. MS calcd. for C₁₂H₁₅NO₂ [(M+H)⁺] 206, obsd. 206.3.

Step 4) E)-2-Azido-3-(4-morpholin-4-ylmethyl-phenyl)-acrylic acid methylester

A mixture of 4-morpholin-4-ylmethyl-benzaldehyde (6.8 g, 33.17 mmol) andazido-acetic acid ethyl ester (7.11 g, 132.68 mmol) in methanol (18 mL)was added to a stirred solution of sodium methoxide (5.37 g, 99.51 mmol)in methanol (30 mL) at 0° C. and stirred for 30 min. The reactionmixture was filtered through sintered funnel and washed with water togive E)-2-azido-3-(4-morpholin-4-ylmethyl-phenyl)-acrylic acid methylester (7 g, 70%) as a white solid. MS calcd. for C₁₅H₁₈N₄O₃ [(M+H)⁺]302, obsd. 303.3.

Step 5) 6-Morpholin-4-ylmethyl-1H-indole-2-carboxylic acid methyl ester

E)-2-Azido-3-(4-morpholin-4-ylmethyl-phenyl)-acrylic acid methyl ester(3.8 g, 12.58 mmol) in xylene (90 mL) was heated to 90° C. for 2 h,cooled to rt and stirred at rt for 12 h. Xylene was evaporated underreduced pressure and purified by column chromatography (silica gel, 2%MeOH/DCM) to give 6-morpholin-4-ylmethyl-1H-indole-2-carboxylic acidmethyl ester (1.9 g, 55%) as a white solid. MS calcd. for C₁₅H₁₈N₂O₃[(M+H)⁺] 275, obsd. 275.2.

Step 6)6-Morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylicacid methyl ester

6-Morpholin-4-ylmethyl-1H-indole-2-carboxylic acid methyl ester (3.6 g,13.13 mmol) in dry THF (10 mL) was added to a stirred solution of sodiumhydride in 60% oil dispersion (1.3 g, 32.84 mmol) in dry THF (20 mL) at0° C. and stirred for 30 min. Para-toluene sulfonyl chloride (5 g, 26.27mmol) in dry THF (10 mL) was added. The reaction mixture was stirred atrt for 12 h. It was quenched with saturated ammonium chloride solutionand extracted with ethyl acetate, dried over anhydrous sodium sulfate,evaporated under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 1% MeOH/DCM) to give6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylicacid methyl ester (3.5 g, 93%) as a white solid. MS calcd. forC₂₂H₂₄N₂O₅S [(M+H)⁺] 429, obsd. 428.9.

Step 7)3-[6-Morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-3-oxo-propionitrile

Butyl lithium (15 ml, 13.55 mmol) was added to a stirred solution ofdiisopropyl amine (1.95 ml, 13.55 mmol) in dry THF (20 mL) at −78° C.and stirred for 30 min. It was added to a stirred solution of6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylicacid methyl ester (2.9 g, 6.77 mmol) and acetonitrile (1.4 mL, 27 mmol)in dry THF (20 mL) at −78° C. and stirred for 30 min. The reactionmixture was quenched with saturated ammonium chloride solution andextracted with ethyl acetate (20 mL×2). The combined organic phases weredried over anhydrous sodium sulfate, evaporated under reduced pressureand purified by column chromatography (silica gel, 2% MeOH/DCM) to give3-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-3-oxo-propionitrile(1.8 g, 90%) as a yellow solid. MS calcd. for C₂₃H₂₃N₃O₄S [(M+H)⁺] 438,obsd. 438.1.

Step 8)(E)-3-Dimethylamino-2-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile

DMF-DMA (3.9 ml, 29.3 mmol) was added to a stirred solution of3-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-3-oxo-propionitrile(3.2 g, 7.32 mmol) in dry toluene (50 mL) at rt and stirred for 12 h.Toluene was evaporated under reduced pressure and purified by columnchromatography (silica gel, 2% MeOH/DCM) to give(E)-3-dimethylamino-2-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(2.5 g, 97%) as a yellow solid. MS calcd. for C₂₆H₂₈N₄O₄S [(M+H)⁺] 493,obsd. 493.3.

Step 9)[5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone

(E)-3-dimethylamino-2-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indole-2-carbonyl]-acrylonitrile(0.15 g, 0.305 mmol)) was added to a stirred solution of(4-phenoxy-phenyl)-hydrazine (0.091 g, 0.457 mmol) in ethanol and heatedat reflux for 16 h. Ethanol was evaporated under reduced pressure andthe crude material was purified by column chromatography (silica gel, 2%MeOH/DCM) to give[5-amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone(0.14 g, 71%) as a yellow solid. MS calcd. for C₃₆H₃₃N₅O₅S [(M+H)⁺]648,obsd. 648.2.

Step 10)[5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone

Cesium carbonate (0.21 g, 0.65 mmol) was added to a stirred solution of[5-amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[6-morpholin-4-ylmethyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone(0.14 g, 0.216 mmol) in mixture of THF: MeOH (7:3) (6 mL) at rt andstirred for 18 h. The solvent was evaporated under reduced pressure andthe crude material was purified by column chromatography (silica gel, 5%MeOH/DCM) to give[5-amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-[6-morpholin-4-ylmethyl-1H-indol-2-yl]-methanone(0.055 g, 52%) as a yellow solid. MS calcd. for C₂₉H₂₇N₅O₃ [(M+H)⁺] 494,obsd. 494.4.

Example 203-{4-[5-Amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile

Step 1) 3-(3-Chloro-4-nitro-phenoxy)-benzonitrile

A mixture of 2-chloro-4-fluoro-1-nitro-benzene (15 g, 85 mmol),3-hydroxybenzonitrile (10.1 g, 85 mmol) and Cs₂CO₃ (30.4 g, 93.5 mmol)in DMF (100 mL) was heated at 120° C. for 1 h. EtOAc was added and themixture was washed with water and brine. The organic layer was dried(Na₂SO₄), filtered, and evaporated to give3-(3-chloro-4-nitro-phenoxy)-benzonitrile (23 g, 99%) as a yellow solid.

Step 2) 3-(4-Amino-3-chloro-phenoxy)-benzonitrile

A solution of tin(II) chloride dihydrate (75.4 g, 335 mmol) in HCl (50mL) was added to a solution of 3-(3-chloro-4-nitro-phenoxy)-benzonitrile(23 g, 83.9 mmol) in MeOH (500 mL) and the mixture was stirred at roomtemperature for 6 h. The mixture was made basic by adding 2 N NaOH, andthe resulting mixture was extracted with EtOAc. The organic layer waswashed with brine, dried (Na₂SO₄), filtered, and evaporated. The residuewas purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to give3-(4-amino-3-chloro-phenoxy)-benzonitrile (13.8 g, 67%) as a yellow oil.

Step 3) 3-(3-Chloro-4-hydrazino-phenoxy)-benzonitrile hydrochloride salt

A mixture of 3-(4-amino-3-chloro-phenoxy)-benzonitrile (5 g, 20.4 mmol)and conc. HCl (30 mL) in MeOH (30 mL) was cooled to −5° C. A solution ofNaNO₂ (1.72 g, 24.5 mmol) in water (2 mL) was added and the mixture wasstirred for 40 min at −5° C. A solution of tin(II) chloride dihydrate(23.1 g, 102 mmol) in HCl (20 mL) was added and the mixture was stirredfor 1 h. The mixture was evaporated and the solid was filtered off anddried under vacuum to give 3-(3-chloro-4-hydrazino-phenoxy)-benzonitrilehydrochloride salt (5.8 g, 96%). This material was used in the next stepwithout further purification.

Step 4) 6-Morpholin-4-ylmethyl-1H-indole-2-carboxylic acid methyl ester

(E)-2-Azido-3-(4-morpholin-4-ylmethyl-phenyl)-acrylic acid methyl ester(303.34 mg, 1.00 mmol), Rh₂(pfb)₄ (dirhodium(II)Tetrakis(perfluorobutyrate)) (52.8 mg, 0.05 mmol) was dissolved inToluene (758 μl) and then heated to 60° C. for 2 days and then 90° C.for 2 h. The reaction mixture was diluted with EtOAc and washed withwater, brine. The combined organic phases were dried over anhydroussodium sulfate. The solvent was removed under reduced pressure and thecrude material was purified by column chromatography (silica gel, 2%MeOH/DCM) to give 6-morpholin-4-ylmethyl-1H-indole-2-carboxylic acidmethyl ester (0.41 g, 50%) as a white solid. MS calcd. for C₁₅H₁₈N₂O₃[(M+H)⁺] 275, obsd. 275.2.

Step 5)6-Morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carboxylicacid methyl ester

NaH in 60% oil dispersion (244 mg, 6.1 mmol) was added in small portionsto a stirred solution of ethyl6-(morpholinomethyl)-1H-indole-2-carboxylate (1.6 g, 5.5 mmol) in dryTHF (6 mL) and DMF (2.5 mL) at 0° C. The reaction mixture was stirredfor 30 min at 0° C. (2-(chloromethoxy)ethyl)trimethylsilane (925 mg,5.55 mmol) was added at 0° C. and then stirred at rt for 1 h. Thereaction mixture was diluted with EtOAc, washed with water and brine.The combined organic phases were dried over anhydrous sodium sulfate.The solvent was removed under reduced pressure and the crude materialwas purified by column chromatography (silica gel, 0-50% EtOAc/Hexanes)to give6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carboxylicacid methyl ester as a yellow oil. MS calcd. for C₂₁H₃₂N₂O₄Si [(M+H)⁺]405, obsd. 405.2.

Step 6)3-[6-Morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-3-oxo-propionitrile

In a 100 mL round-bottomed flask,6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carboxylicacid methyl ester (1.6 g, 3.82 mmol) and MeCN (941 mg, 1.2 mL, 22.9mmol) were combined with THF (20 mL) to give a dark brown solution.After cooling at −78° C., LDA (2M/THF) (3.82 mL, 7.64 mmol) was addedslowly over 5 min. The reaction mixture was stirred at −78° C. for 30min. The reaction was quenched with Sat. NH₄Cl (10 mL). The reaction wasdiluted with water (150 mL), extracted with EtOAc (100 mL) and washedwith brine. The combined organic phases were dried over anhydrous sodiumsulfate and the solvent was removed under reduced pressure. The crudematerial was purified by column chromatography (silica gel, 0-40%EtOAc/Hexanes) to give3-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-3-oxo-propionitrile(0.15 g, 10%) as a yellow oil. MS calcd. for C₂₂H₃₁N₃O₃Si [(M+H)⁺] 414,obsd. 414.3.

Step 7)(E)-3-Dimethylamino-2-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-acrylonitrile

In a 25 mL round-bottomed flask, give3-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-yl]-3-oxo-propionitrile(145 mg, 351 μmol) was combined with toluene (1.46 mL) to give a lightyellow solution. N,N-dimethylformamide dimethyl acetal (60.5 μl, 456μmol) was added and stirred at room temperature for 30 min. The solventwas removed under reduced pressure. The crude material was purified bycolumn chromatography (silica gel, 0-50% EtOAc/Hexanes) to give(E)-3-dimethylamino-2-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-acrylonitrile(0.12 g, 73%) as a yellow oil. MS calcd. for C₂₅H₃₆N₄O₃Si [(M+H)⁺] 469,obsd. 469.2.

Step 8)3-(4-{5-Amino-4-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-chloro-phenoxy)-benzonitrile

(E)-3-dimethylamino-2-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-acrylonitrile(115 mg, 245 μmol), 3-(3-Chloro-4-hydrazino-phenoxy)-benzonitrilehydrochloride salt (218 mg, 736 μmol) and K₂CO₃ (170 mg, 1.23 mmol) inEtOH (2 mL) were heated at 80° C. for 2 h. The reaction mixture wasdiluted with EtOAc and washed with water, brine and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure and thecrude material was purified by column chromatography (silica gel, 0-50%EtOAc/Hexanes) to give3-(4-{5-Amino-4-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-chloro-phenoxy)-benzonitrile(0.103 g, 61%) as a yellow oil. MS calcd. for C₃₆H₃₉ClN₆O₄Si [(M+H)⁺]683, obsd. 683.2.

Step 10)3-{4-[5-Amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile

3-(4-{5-Amino-4-[6-morpholin-4-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole-2-carbonyl]-pyrazol-1-yl}-3-chloro-phenoxy)-benzonitrile(80 mg, 117 μmol) was dissolved in EtOH (4 mL) and HCl 10% (2 mL, 20.0mmol) was added and heated to 80° C. for 10 min. The solvent was removedunder reduced pressure. The crude material was triturated with ether togive3-{4-[5-amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile(80 mg, 94% yield). ¹H NMR (DMSO-d₆) δ: 12.13 (s, 1H), 8.45 (s, 1H),7.89 (d, J=8.3 Hz, 1H), 7.72-7.86 (m, 6H), 7.58-7.70 (m, 3H), 7.42 (d,J=8.3 Hz, 1H), 7.36 (dd, J=8.7, 2.6 Hz, 1H), 7.25 (br. s., 1H), 4.57 (d,J=4.8 Hz, 2H), 3.77-4.14 (m, 4H), 3.16-3.45 (m, 4H).

Biological Examples

Bruton's Tyrosine Kinase (Btk) Inhibition Assay

The assay is a capture of radioactive ³³P phosphorylated product throughfiltration. The interactions of Btk, biotinylated SH₂ peptide substrate(Src homology), and ATP lead to phosphorylation of the peptidesubstrate. Biotinylated product is bound streptavidin sepharose beads.All bound, radiolabeled products are detected by scintillation counter.

Plates assayed are 96-well polypropylene (Greiner) and 96-well 1.2 μmhydrophilic PVDF filter plates (Millipore). Concentrations reported hereare final assay concentrations: 10-100 μM compounds in DMSO (Burdick andJackson), 5-10 nM Btk enzyme (His-tagged, full-length), 30 μM peptidesubstrate (Biotin-Aca-AAAEEIYGEI-NH₂), 100 μM ATP (Sigma), 8 mMimidazole (Sigma, pH 7.2), 8 mM glycerol-2-phosphate (Sigma), 200 μMEGTA (Roche Diagnostics), 1 mM MnCl₂ (Sigma), 20 mM mgCl₂ (Sigma), 0.1mg/mL BSA (Sigma), 2 mM DTT (Sigma), 1 μCi ³³P ATP (Amersham), 20%streptavidin sepharose beads (Amersham), 50 mM EDTA (Gibco), 2 M NaCl(Gibco), 2 M NaCl w/1% phosphoric acid (Gibco), microscint-20 (PerkinElmer).

IC₅₀ determinations are calculated from 10 data points per compoundutilizing data produced from a standard 96-well plate assay template.One control compound and seven unknown inhibitors were tested on eachplate and each plate was run twice. Typically, compounds were diluted inhalf-log starting at 100 μM and ending at 3 nM. The control compound wasstaurosporine. Background was counted in the absence of peptidesubstrate. Total activity was determined in the presence of peptidesubstrate. The following protocol was used to determine Btk inhibition.

Sample preparation: The test compounds were diluted at half-logincrements in assay buffer (imidazole, glycerol-2-phosphate, EGTA,MnCl₂, mgCl₂, BSA).

Bead Preparation

1) Rinse beads by centrifuging at 500 g

2) Reconstitute the beads with PBS and EDTA to produce a 20% bead slurry

3) Pre-incubate reaction mix without substrate (assay buffer, DTT, ATP,³³P ATP) and mix with substrate (assay buffer, DTT, ATP, ³³P ATP,peptide substrate) 30° C. for 15 min.

4) To start assay, pre-incubate 10 μL Btk in enzyme buffer (imidazole,glycerol-2-phosphate, BSA) and 10 μL of test compounds for 10 min at RT.

5) Add 30 μL reaction mixture without or with substrate to Btk andcompounds.

6) Incubate 50 μL total assay mix for 30 min at 30° C.

7) Transfer 40 μL of assay to 150 μL bead slurry in filter plate to stopreaction.

8) Wash filter plate after 30 min, with following steps

3×250 μL NaCl

3×250 μL NaCl containing 1% phosphoric acid

1×250 μL H₂O

9) Dry plate for 1 h at 65° C. or overnight at RT

10) Add 50 μL microscint-20 and count ³³P cpm on scintillation counter.

Calculate percent activity from raw data in cpmpercent activity=(sample−bkg)/(total activity−bkg)×100Calculate IC₅₀ from percent activity, using one-site dose responsesigmoidal modely=A+((B−A)/(1+((x/C)^(D)))))x=cmpd conc, y=% activity, A=min, B=max, C=IC₅₀, D=1 (hill slope)Bruton's Tyrosine Kinase (BTK) Inhibition TR-FRET (Time Resolved FRET)Assay

This BTK competition assay measures compound potency (IC50) for theinactivated state of Bruton's Tyrosine Kinase using FRET(Förster/Flouresence Resonance Energy Transfer) technology. The BTK-Eucomplex was incubated on ice one hour prior to use at a startingconcentration of 50 nM BTK-Bioease™: 10 nM Eu-streptavidin (Perkin-ElmerCatalog# AD0062). The assay buffer consisted of 20 mM HEPES (pH 7.15),0.1 mM DTT, 10 mM MgCl₂, 0.5 mg/ml BSA with 3% Kinase Stabilizer(Fremont Biosolutions, Catalog # STB-K02). After 1 h, the reactionmixture from above was diluted 10 fold in assay buffer to make 5 nM BTK:1 nM Eu-Streptavidin complex (donor fluorophore). 18 μl of a mixture of0.11 nM BTK-Eu and 0.11 nM Kinase Tracer 178 (Invitrogen, Catalog #PV5593) with BTK-Eu alone as no negative control, was then dispensedinto 384-well flat bottom plates (Greiner, 784076). Compounds to betested in assay were prepared as 10× concentrations and serial dilutionin half-log increments was performed in DMSO so as to generate 10 pointcurves. To initiate the FRET reaction, compounds prepared as 10× stockin DMSO was added to the plates and the plates were incubated 18-24 h at14° C.

After the incubation the plates were read on a BMG Pherastar Fluorescentplate reader (or equivalent) and used to measure the emission energyfrom the europium donor fluorophore (620 nm emission) and the FRET (665nm emission). The negative control well values were averaged to obtainthe mean minimum. The positive “no inhibitor” control wells wereaveraged to obtain the mean maximum. Percent of maximal FRET wascalculated using following equation:% maxFRET=100×[(FSR_(cmpd)−FSR_(mean min))/(FSR_(mean max)−FSR_(mean min))]where FSR=FRET Signal ratio. % Max FRET curves were plotted in ActivityBase (Excel) and the IC50(%), hill slope, z′ and % CV were determined.The mean IC50 and standard deviation will be derived from duplicatecurves (singlet inhibition curves from two independent dilutions) usingMicrosoft Excel.

Representative compound data for this assay are listed below in TableII.

TABLE II Compound FRET IC50 (μmol) Radiometric IC50 (μmol) I-1 0.041 I-20.869 I-3 0.502 I-4 21.95 I-5 0.216 I-6 1.0 I-7 0.552 I-8 0.059 I-90.146 I-10 0.162 I-11 73.85 I-12 >1 I-13 >1 I-14 0.003 I-15 0.007 I-160.082 I-17 0.230 I-18 0.005 I-19 0.0005 I-20 0.001Inhibition of B Cell Activation in Whole Blood Measured by CD69Expression

A procedure to test the ability of Btk inhibitors to suppress B cellreceptor-mediated activation of B cells in human blood is as follows:

Human whole blood (HWB) is obtained from healthy volunteers, with thefollowing restrictions: 24 hr drug-free, non-smokers. Blood is collectedby venipuncture into Vacutainer tubes anticoagulated with sodiumheparin. Test compounds are diluted to ten times the desired startingdrug concentration in PBS (20×), followed by three-fold serial dilutionsin 10% DMSO in PBS to produce a nine point dose-response curve. 5.5 μlof each compound dilution is added in duplicate to a 2 mL 96-well Vbottom plate (Analytical Sales and Services, #59623-23); 5.5 μl of 10%DMSO in PBS is added to control and no-stimulus wells. HWB (1000 isadded to each well, and after mixing the plates are incubated at 37 C,5% CO₂, 100% humidity for 30 minutes. Goat F (ab′)2 anti-human IgM(Southern Biotech, #2022-14) (10 μl of a 500 μg/mL solution, 50 μg/mLfinal concentration) is added to each well (except the no-stimuluswells) with mixing and the plates are incubated for an additional 20hours.

At the end of the 20 hour incubation, samples are incubated withflorescent-probe-labeled antibodies (15 μL PE Mouse anti-Human CD20, BDPharmingen, #555623, and/or 20 μL APC Mouse anti-Human CD69, BDPharmingen #555533) for 30 minutes, at 37 C, 5% CO₂, 100% humidity.Included are induced control, unstained and single stains forcompensation adjustments and initial voltage settings. Samples are thenlysed with 1 mL of 1× Pharmingen Lyse Buffer (BD Pharmingen #555899),and plates are centrifuged at 1800 rpm for 5 minutes. Supernatants areremoved via suction and the remaining pellets are lysed again withanother 1 mL of 1× Pharmingen Lyse Buffer, and plates are spun down asbefore. Supernatants are aspirated and remaining pellets are washed inFACs buffer (PBS+1% FBS). After a final spin, the supernantants areremoved and pellets are resuspended in 180 μL of FACs buffer. Samplesare transferred to a 96 well plate suitable to be run on the HTS 96 wellsystem on the BD LSR II flow cytometer.

Using appropriate excitation and emission wavelengths for thefluorophores used, data are acquired and percent positive cell valuesare obtained using Cell Quest Software. Results are initially analyzedby FACS analysis software (Flow Jo). The IC50 for test compounds isdefined as the concentration which decreases by 50% the percentage ofCD69-positive cells that are also CD20-positive after stimulation byanti-IgM (average of 8 control wells, after subtraction of the averageof 8 wells for the no-stimulus background). The IC50 values arecalculated using XLfit software version 3, equation 201.

Inhibition of B-Cell Activation-B Cell FLIPR Assay in Ramos Cells

Inhibition of B-cell activation by compounds of the present invention isdemonstrated by determining the effect of the test compounds on anti-IgMstimulated B cell responses.

The B cell FLIPR assay is a cell based functional method of determiningthe effect of potential inhibitors of the intracellular calcium increasefrom stimulation by an anti-IgM antibody. Ramos cells (human Burkitt'slymphoma cell line. ATCC-No. CRL-1596) were cultivated in Growth Media(described below). One day prior to assay, Ramos cells were resuspendedin fresh growth media (same as above) and set at a concentration of0.5×10⁶ cells/mL in tissue culture flasks. On day of assay, cells arecounted and set at a concentration of 1×10⁶ cells/mL in growth mediasupplemented with 1 μM FLUO-3AM (TefLabs Cat-No. 0116, prepared inanhydrous DMSO and 10% Pluronic acid) in a tissue culture flask, andincubated at 37° C. (4% CO₂) for 1 h. To remove extracellular dye, cellswere collected by centrifugation (5 min, 1000 rpm), resuspended in FLIPRbuffer (described below) at 1×10⁶ cells/mL and then dispensed into96-well poly-D-lysine coated black/clear plates (BD Cat-No. 356692) at1×10⁵ cells per well. Test compounds were added at variousconcentrations ranging from 100 μM to 0.03 μM (7 concentrations, detailsbelow), and allowed to incubate with cells for 30 min at RT. Ramos cellCa²⁺ signaling was stimulated by the addition of 10 μg/mL anti-IgM(Southern Biotech, Cat-No. 2020-01) and measured on a FLIPR (MolecularDevices, captures images of 96 well plates using a CCD camera with anargon laser at 480 nM excitation).

Media/Buffers:

Growth Medium: RPMI 1640 medium with L-glutamine (Invitrogen, Cat-No.61870-010), 10% Fetal Bovine Serum (FBS, Summit Biotechnology Cat-No.FP-100-05); 1 mM Sodium Pyruvate (Invitrogen Cat. No. 11360-070).

FLIPR buffer: HBSS (Invitrogen, Cat-No. 141175-079), 2 mM CaCl₂ (SigmaCat-No. C-4901), HEPES (Invitrogen, Cat-No. 15630-080), 2.5 mMProbenecid (Sigma, Cat-No. P-8761), 0.1% BSA (Sigma, Cat-No. A-7906), 11mM Glucose (Sigma, Cat-No. G-7528)

Compound Dilution Details:

In order to achieve the highest final assay concentration of 100 μM, 24μL of 10 mM compound stock solution (made in DMSO) is added directly to576 μL of FLIPR buffer. The test compounds are diluted in FLIPR Buffer(using Biomek 2000 robotic pipettor) resulting in the following dilutionscheme: vehicle, 1.00×10⁻⁴ M, 1.00×10⁻⁵, 3.16×10⁻⁶, 1.00×10⁻⁶,3.16×10⁻⁷, 1.00×10⁻⁷, 3.16×10⁻⁸.

Assay and Analysis:

Intracellular increases in calcium were reported using a max-minstatistic (subtracting the resting baseline from the peak caused byaddition of the stimulatory antibody using a Molecular Devices FLIPRcontrol and statistic exporting software. The IC₅₀ was determined usinga non-linear curve fit (GraphPad Prism software).

Mouse Collagen-Induced Arthritis (mCIA)

On day 0 mice are injected at the base of the tail or several spots onthe back with an emulsion of Type II Collagen (i.d.) in CompleteFreund's adjuvant (CFA). Following collagen immunization, animals willdevelop arthritis at around 21 to 35 days. The onset of arthritis issynchronized (boosted) by systemic administration of collagen inIncomplete Freund's adjuvant (IFA; i.d.) at day 21. Animals are examineddaily after day 20 for any onset of mild arthritis (score of 1 or 2; seescore description below) which is the signal to boost. Following boost,mice are scored and dosed with candidate therapeutic agents for theprescribed time (typically 2-3 weeks) and dosing frequency, daily (QD)or twice-daily (BID).

Rat Collagen-Induced Arthritis (rCIA)

On day 0, rats are injected with an emulsion of Bovine Type II Collagenin Incomplete Freund's adjuvant (IFA) is injected intradermally (i.d.)on several locations on the back. A booster injection of collagenemulsion is given around day 7, (i.d.) at the base of the tail oralternative sites on the back. Arthritis is generally observed 12-14days after the initial collagen injection. Animals may be evaluated forthe development of arthritis as described below (Evaluation ofarthritis) from day 14 onwards. Animals are dosed with candidatetherapeutic agents in a preventive fashion starting at the time ofsecondary challenge and for the prescribed time (typically 2-3 weeks)and dosing frequency, daily (QD) or twice-daily (BID).

Evaluation of Arthritis:

In both models, developing inflammation of the paws and limb joints isquantified using a scoring system that involves the assessment of the 4paws following the criteria described below:

Scoring:

-   -   1=swelling and/or redness of paw or one digit.    -   2=swelling in two or more joints.    -   3=gross swelling of the paw with more than two joints involved.    -   4=severe arthritis of the entire paw and digits.

Evaluations are made on day 0 for baseline measurement and startingagain at the first signs or swelling for up to three times per weekuntil the end of the experiment. The arthritic index for each mouse isobtained by adding the four scores of the individual paws, giving amaximum score of 16 per animal.

Rat In Vivo Asthma Model

Male Brown-Norway rats are sensitized i.p. with 100 μg of OA (ovalbumin)in 0.2 mL alum once every week for three weeks (day 0, 7, and 14). Onday 21 (one week following last sensitization), the rats are dosed q.d.with either vehicle or compound formulation subcutaneously 0.5 hourbefore OA aerosol challenge (1% OA for 45 minutes) and terminated 4 or24 hours after challenge. At time of sacrifice, serum and plasma arecollected from all animals for serology and PK, respectively. A trachealcannula is inserted and the lungs are lavaged 3× with PBS. The BAL fluidis analyzed for total leukocyte number and differential leukocytecounts. Total leukocyte number in an aliquot of the cells (20-100 μL) isdetermined by Coulter Counter. For differential leukocyte counts, 50-200μL of the sample is centrifuged in a Cytospin and the slide stained withDiff-Quik. The proportions of monocytes, eosinophils, neutrophils andlymphocytes are counted under light microscopy using standardmorphological criteria and expressed as a percentage. Representativeinhibitors of Btk show decreased total leucocyte count in the BAL of OAsensitized and challenged rats as compared to control levels.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

The invention claimed is:
 1. A compound of Formula I,

wherein: R¹ is lower alkyl, phenyl, cycloalkyl, or pyridyl, optionallysubstituted with one or more R^(1′); each R^(1′) is independently loweralkyl, halo, —C(═O)NH₂, or cyano; R² is hydrogen, halo, lower alkoxy,hydroxy, or lower alkyl; R³ is hydrogen, halo, lower alkoxy, hydroxy, orlower alkyl; R⁴ is hydrogen or heterocycloalkyl lower alkylenyl; X is CHor N; and Y is CH or N; or a pharmaceutically acceptable salt thereof.2. The compound of claim 1, wherein Y is CH.
 3. The compound of claim 1,wherein X is N.
 4. The compound of claim 1, wherein X is CH.
 5. Thecompound of claim 1, wherein R⁴ morpholinyl methylene.
 6. The compoundof claim 1, wherein R⁴ is hydrogen.
 7. The compound of claim 1, whereinR² is hydrogen.
 8. The compound of claim 1, wherein R² is halo.
 9. Thecompound of claim 1, wherein R² is lower alkyl.
 10. The compound ofclaim 1, wherein R² is lower alkoxy.
 11. The compound of claim 1,wherein R² is hydroxy.
 12. The compound of claim 1, wherein R³ is halo,lower alkoxy, or hydroxy.
 13. The compound of claim 1, wherein R¹ isphenyl, optionally substituted with one or more R^(1′).
 14. The compoundof claim 1, wherein R¹ is lower alkyl, cycloalkyl, or heteroaryl,optionally substituted with one or more R^(1′).
 15. A compound, selectedfrom the group consisting of:[5-Amino-1-(3-fluoro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;[5-Amino-1-(6-phenoxy-pyridin-3-yl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;{5-Amino-1-[4-(pyridin-2-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;{5-Amino-1-[4-(pyridin-3-yloxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;5-Amino-1-(3-chloro-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;{5-Amino-1-[4-(3,4-difluoro-phenoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;[5-Amino-1-(3-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;[5-Amino-1-(3-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;[5-Amino-1-(2-methoxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;[5-Amino-1-(2-hydroxy-4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;[5-Amino-1-(4-isopropoxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;[5-Amino-1-(4-cyclopentyloxy-phenyl)-1H-pyrazol-4-yl]-(1H-indol-2-yl)-methanone;{5-Amino-1-[4-(2,2-dimethyl-propoxy)-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-indol-2-yl)-methanone;2-{(4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzonitrile;3-{4-[5-Amino-4-(1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile;3-{4-[5-Amino-4-(1H-benzoimidazole-2-carbonyl)-pyrazol-1-yl]-3-methyl-phenoxy}-benzamide;{5-Amino-1-[4-(2,3-difluoro-phenoxy)-2-methyl-phenyl]-1H-pyrazol-4-yl}-(1H-benzoimidazol-2-yl)-methanone;[5-Amino-1-(4-phenoxy-phenyl)-1H-pyrazol-4-yl]-(6-morpholin-4-ylmethyl-1H-indol-2-yl)-methanone;and3-{4-[5-Amino-4-(6-morpholin-4-ylmethyl-1H-indole-2-carbonyl)-pyrazol-1-yl]-3-chloro-phenoxy}-benzonitrile,or a pharmaceutically acceptable salt thereof.
 16. A method for treatingan inflammatory condition mediated by Bruton's tyrosine kinase,comprising the step of administering to a patient in need thereof atherapeutically effective amount of the compound of claim
 1. 17. Amethod for treating rheumatoid arthritis, comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of the compound of claim
 1. 18. A method for treating asthma,comprising the step of administering to a patient in need thereof atherapeutically effective amount of the compound of claim
 1. 19. Apharmaceutical composition, comprising the compound of claim 1, admixedwith at least one pharmaceutically acceptable carrier, excipient ordiluent.
 20. A pharmaceutical composition, comprising the compound ofclaim 15, admixed with at least one pharmaceutically acceptable carrier,excipient or diluent.
 21. A method for treating an inflammatorycondition mediated by Bruton's tyrosine kinase, comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of the compound of claim
 15. 22. A method for treating rheumatoidarthritis, comprising the step of administering to a patient in needthereof a therapeutically effective amount of the compound of claim 15.23. A method for treating asthma, comprising the step of administeringto a patient in need thereof a therapeutically effective amount of thecompound of claim 15.